JP5895011B2 - 7-Unsubstituted indole Mcl-1 inhibitors - Google Patents

Description

  The present invention relates to a compound that inhibits the activity of anti-apoptotic Mcl-1 protein, a composition containing the compound, and a method for treating a disease involving overexpressed or unregulated Mcl-1 protein.

  Mcl-1 protein is associated with many diseases. Accordingly, there remains a need in the therapeutic field for compounds that bind to Mcl-1 protein and inhibit its activity.

  Accordingly, one embodiment of the present invention relates to compounds having the following Formula I that inhibit the activity of Mcl-1 protein, as well as therapeutically acceptable salts thereof:

式中、
Ｌ^１は結合であるか、アルキレン、アルケニレンまたはアルキニレンであり；
Ａ^１はＣ（Ｏ）ＯＨまたはそれの生物学的等価体であるか、Ｃ（Ｏ）ＯＲ^１、Ｃ（Ｏ）ＯＲ^２、Ｃ（Ｏ）ＯＲ^３またはＣ（Ｏ）ＯＲ^４であり；
Ｂ^１、Ｃ^１、Ｄ^１、Ｅ^１およびＦ^１のうちの１、２、３、４個またはそれぞれは独立に、Ｒ^１、Ｒ^２、Ｒ^３もしくはＲ^４、ＯＲ^１、ＳＲ^１、Ｓ（Ｏ）Ｒ^１、ＳＯ_２Ｒ^１、ＮＨ_２、ＮＨＲ^１、Ｎ（Ｒ^１）_２、Ｃ（Ｏ）Ｒ^１、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^１、Ｃ（Ｏ）Ｎ（Ｒ^１）_２、ＮＨＣ（Ｏ）Ｒ^１、ＮＲ^１Ｃ（Ｏ）Ｒ^１、ＮＨＳＯ_２Ｒ^１、ＮＲ^１ＳＯ_２Ｒ^１、ＮＨＣ（Ｏ）ＯＲ^１、ＮＲ^１Ｃ（Ｏ）ＯＲ^１、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^１、ＳＯ_２Ｎ（Ｒ^１）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^１ＮＨＣ（Ｏ）Ｎ（Ｒ^１）_２、ＮＲ^１Ｃ（Ｏ）Ｎ（Ｒ^１）_２、ＯＲ^２、ＳＲ^２、Ｓ（Ｏ）Ｒ^２、ＳＯ_２Ｒ^２、ＮＨ_２、ＮＨＲ^２、Ｎ（Ｒ^２）_２、Ｃ（Ｏ）Ｒ^２、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^２、Ｃ（Ｏ）Ｎ（Ｒ^２）_２、ＮＨＣ（Ｏ）Ｒ^２、ＮＲ^２Ｃ（Ｏ）Ｒ^２、ＮＨＳＯ_２Ｒ^２、ＮＲ^２ＳＯ_２Ｒ^２、ＮＨＣ（Ｏ）ＯＲ^２、ＮＲ^２Ｃ（Ｏ）ＯＲ^２、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^２、ＳＯ_２Ｎ（Ｒ^２）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^２ＮＨＣ（Ｏ）Ｎ（Ｒ^２）_２、ＮＲ^１Ｃ（Ｏ）Ｎ（Ｒ^２）_２、ＯＲ^３、ＳＲ^３、Ｓ（Ｏ）Ｒ^３、ＳＯ_２Ｒ^３、ＮＨ_２、ＮＨＲ^３、Ｎ（Ｒ^３）_２、Ｃ（Ｏ）Ｒ^３、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^３、Ｃ（Ｏ）Ｎ（Ｒ^３）_２、ＮＨＣ（Ｏ）Ｒ^３、ＮＲ^２Ｃ（Ｏ）Ｒ^３、ＮＨＳＯ_２Ｒ^３、ＮＲ^３ＳＯ_２Ｒ^３、ＮＨＣ（Ｏ）ＯＲ^３、ＮＲ^３Ｃ（Ｏ）ＯＲ^３、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^３、ＳＯ_２Ｎ（Ｒ^３）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^３ＮＨＣ（Ｏ）Ｎ（Ｒ^３）_２、ＮＲ^１Ｃ（Ｏ）Ｎ（Ｒ^３）_２、ＯＲ^４、ＳＲ^４、Ｓ（Ｏ）Ｒ^４、ＳＯ_２Ｒ^４、ＮＨ_２、ＮＨＲ^４、Ｎ（Ｒ^４）_２、Ｃ（Ｏ）Ｒ^４、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^４、Ｃ（Ｏ）Ｎ（Ｒ^４）_２、ＮＨＣ（Ｏ）Ｒ^４、ＮＲ^４Ｃ（Ｏ）Ｒ^４、ＮＨＳＯ_２Ｒ^４、ＮＲ^４ＳＯ_２Ｒ^４、ＮＨＣ（Ｏ）ＯＲ^４、ＮＲ^４Ｃ（Ｏ）ＯＲ^４、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^４、ＳＯ_２Ｎ（Ｒ^４）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^４、ＮＨＣ（Ｏ）Ｎ（Ｒ^４）_２またはＮＲ^１Ｃ（Ｏ）Ｎ（Ｒ^４）_２であり、残りのものはＨ、ＯＨ、ＣＮ、Ｆ、Ｃｌ、ＢｒまたはＩであり；
Ｒ^１は、縮合していないかベンゼン、ヘテロアレンまたはＲ^１Ａと縮合しているフェニルであり；Ｒ^１Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^２は、縮合していないかベンゼン、ヘテロアレンまたはＲ^２Ａと縮合しているヘテロアリールであり；Ｒ^２Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^３は、それぞれ縮合していないかベンゼン、ヘテロアレンまたはＲ^３Ａと縮合しているシクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり；Ｒ^３Ａはシクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^４は、アルキル、アルケニルまたはアルキニルであって、それぞれ置換されていないか１、２、３、４もしくは５個の独立に選択されるＲ^５、ＯＲ^５、ＳＲ^５、Ｓ（Ｏ）Ｒ^５、ＳＯ_２Ｒ^５、ＮＨ_２、ＮＨＲ^５、Ｎ（Ｒ^５）_２、Ｃ（Ｏ）Ｒ^５、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^５、Ｃ（Ｏ）Ｎ（Ｒ^５）_２、ＮＨＣ（Ｏ）Ｒ^５、ＮＲ^５Ｃ（Ｏ）Ｒ^５、ＮＨＳＯ_２Ｒ^５、ＮＲ^５ＳＯ_２Ｒ^５、ＮＨＣ（Ｏ）ＯＲ^５、ＮＲ^５Ｃ（Ｏ）ＯＲ^５、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^５、ＳＯ_２Ｎ（Ｒ^５）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^５、ＮＨＣ（Ｏ）Ｎ（Ｒ^５）_２、ＮＲ^５Ｃ（Ｏ）Ｎ（Ｒ^５）_２、ＯＨ、（Ｏ）、Ｃ（Ｏ）ＯＨ、ＣＮ、ＣＦ_３、ＯＣＦ_３、ＣＦ_２ＣＦ_３、Ｆ、Ｃｌ、ＢｒまたはＩで置換されており；
Ｒ^５は、Ｒ^６、Ｒ^７、Ｒ^８またはＲ^９であり；
Ｒ^６は、縮合していないかベンゼン、ヘテロアレンまたはＲ^６Ａと縮合しているフェニルであり；Ｒ^６Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^７は、縮合していないかベンゼン、ヘテロアレンまたはＲ^７Ａと縮合しているヘテロアリールであり；Ｒ^７Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^８は、それぞれ縮合していないかベンゼン、ヘテロアレンまたはＲ^８Ａと縮合しているシクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり；Ｒ^８Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^９は、それぞれ置換されていないか１、２、３、４もしくは５個の独立に選択されるＲ^９Ａ、ＯＲ^９Ａ、ＳＲ^９Ａ、Ｓ（Ｏ）Ｒ^９Ａ、ＳＯ_２Ｒ^９Ａ、ＮＨ_２、ＮＨＲ^９Ａ、Ｎ（Ｒ^９Ａ）_２、Ｃ（Ｏ）Ｒ^９Ａ、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^９Ａ、Ｃ（Ｏ）Ｎ（Ｒ^９Ａ）_２、ＮＨＣ（Ｏ）Ｒ^９Ａ、ＮＲ^９ＡＣ（Ｏ）Ｒ^９Ａ、ＮＨＳＯ_２Ｒ^９Ａ、ＮＲ^９ＡＳＯ_２Ｒ^９Ａ、ＮＨＣ（Ｏ）ＯＲ^９Ａ、ＮＲ^９ＡＣ（Ｏ）ＯＲ^９Ａ、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^９Ａ、ＳＯ_２Ｎ（Ｒ^９Ａ）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^９ＡＮＨＣ（Ｏ）Ｎ（Ｒ^９Ａ）_２、ＮＲ^９ＡＣ（Ｏ）Ｎ（Ｒ^９Ａ）_２、ＯＨ、（Ｏ）、Ｃ（Ｏ）ＯＨ、ＣＮ、ＣＦ_３、ＯＣＦ_３、ＣＦ_２ＣＦ_３、Ｆ、Ｃｌ、ＢｒまたはＩで置換されているアルキル、アルケニルまたはアルキニルであり；
Ｒ^９Ａは、Ｒ^９Ｂ、Ｒ^９ＣまたはＲ^９Ｄであり；
Ｒ^９Ｂは、縮合していないかベンゼン、ヘテロアレンまたはＲ^９Ｂ２と縮合しているフェニルであり；Ｒ^９Ｂ２は、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^９Ｃは、縮合していないかベンゼン、ヘテロアレンまたはＲ^９Ｃ２と縮合しているヘテロアリールであり；Ｒ^９Ｃ２は、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^９Ｄは、それぞれ縮合していないかベンゼン、ヘテロアレンまたはＲ^９Ｄ２と縮合しているシクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり、；Ｒ^９Ｄ２は、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
前記各環状部分は独立に、置換されていないか１もしくは２もしくは３もしくは４もしくは５個の独立に選択されるＲ^１０、ＯＲ^１０、ＯＣＨ_２Ｒ^１０、ＳＲ^１０、Ｓ（Ｏ）Ｒ^１０、ＳＯ_２Ｒ^１０、Ｃ（Ｏ）Ｒ^１０、ＣＯ（Ｏ）Ｒ^１０、ＯＣ（Ｏ）Ｒ^１０、ＯＣ（Ｏ）ＯＲ^１０、ＮＯ_２、ＮＨ_２、ＮＨＲ^１０、Ｎ（Ｒ^１０）_２、ＣＨ_２Ｒ^１０、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^１０、Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、ＮＨＣ（Ｏ）Ｒ^１０、ＮＲ^１０Ｃ（Ｏ）Ｒ^１０、Ｃ（Ｏ）ＮＨＯＨ、Ｃ（Ｏ）ＮＨＯＲ^１０、Ｃ（Ｏ）ＮＨＳＯ_２Ｒ^１０、Ｃ（Ｏ）ＮＲ^１０ＳＯ_２Ｒ^１０、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^１０、ＳＯ_２Ｎ（Ｒ^１０）_２、ＣＦ_３、ＣＦ_２ＣＦ_３、Ｃ（Ｏ）Ｈ、Ｃ（Ｏ）ＯＨ、Ｃ（Ｎ）ＮＨ_２、Ｃ（Ｎ）ＮＨＲ^１０、Ｃ（Ｎ）Ｎ（Ｒ^１０）_２、＝ＮＯ−（アルキレン）−Ｃ（Ｏ）ＣＦ_３、ＣＮＯＨ、ＣＮＯＣＨ_３、ＯＨ、（Ｏ）、Ｎ_３、ＣＦ_３、ＣＦ_２ＣＦ_３、ＯＣＦ_３、ＯＣＦ_２ＣＦ_３、Ｆ、Ｃｌ、ＢｒもしくはＩで置換されており；
Ｒ^１０は、Ｒ^１１、Ｒ^１２、Ｒ^１３またはＲ^１４であり；
Ｒ^１１は、縮合していないかベンゼン、ヘテロアレンまたはＲ^１１Ａと縮合しているフェニルであり；Ｒ^１１Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^１２は、縮合していないかベンゼン、ヘテロアレンまたはＲ^１２Ａと縮合しているヘテロアリールであり；Ｒ^１２Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^１３は、それぞれ縮合していないかベンゼン、ヘテロアレンまたはＲ^１３Ａと縮合しているシクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり；Ｒ^１３Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^１４は、それぞれ置換されていないか１、２、３、４もしくは５個の独立に選択されるＲ^１５、ＯＲ^１５、ＳＲ^１５、Ｓ（Ｏ）Ｒ^１５、ＳＯ_２Ｒ^１５、ＮＨ_２、ＮＨＲ^１５、Ｎ（Ｒ^１５）_２、Ｃ（Ｏ）Ｒ^１５、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^１５、Ｃ（Ｏ）Ｎ（Ｒ^１５）_２、ＮＨＣ（Ｏ）Ｒ^１５、ＮＲ^１５Ｃ（Ｏ）Ｒ^１５、ＮＨＳＯ_２Ｒ^１５、ＮＲ^１５ＳＯ_２Ｒ^１５、ＮＨＣ（Ｏ）ＯＲ^１５、ＮＲ^１５Ｃ（Ｏ）ＯＲ^１５、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^１５、ＳＯ_２Ｎ（Ｒ^１５）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^１５、ＮＨＣ（Ｏ）Ｎ（Ｒ^１５）_２、ＮＲ^１５Ｃ（Ｏ）Ｎ（Ｒ^１５）_２、ＯＨ、（Ｏ）、Ｃ（Ｏ）ＯＨ、ＣＮ、ＣＦ_３、ＯＣＦ_３、ＣＦ_２ＣＦ_３、Ｆ、Ｃｌ、ＢｒまたはＩで置換されているアルキル、アルケニルまたはアルキニルであり；
Ｒ^１５は、Ｒ^１６、Ｒ^１７、Ｒ^１８またはＲ^１９であり；
Ｒ^１６は、縮合していないかベンゼン、ヘテロアレンまたはＲ^１５Ａと縮合しているフェニルであり；Ｒ^１５Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^１７は、縮合していないかベンゼン、ヘテロアレンまたはＲ^１６Ａと縮合しているヘテロアリールであり；Ｒ^１６Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^１８は、それぞれ縮合していないかベンゼン、ヘテロアレンまたはＲ^１８Ａと縮合しているシクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり；Ｒ^１８Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^１９は、それぞれ置換されていないかＲ^２０で置換されているアルキル、アルケニルまたはアルキニルであり；
Ｒ^２０は、フェニル、ヘテロアリール、シクロアルキル、シクロアルケニルまたは複素環アルキルであり；
Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｒ^１６、Ｒ^１７およびＲ^１８は独立に、置換されていないか１もしくは２もしくは３もしくは４もしくは５個の独立のＲ^２１、ＯＲ^２１、ＯＣＨ_２Ｒ^２１、ＳＲ^２１、Ｓ（Ｏ）Ｒ^２１、ＳＯ_２Ｒ^２１、Ｃ（Ｏ）Ｒ^２１、ＣＯ（Ｏ）Ｒ^２１、ＯＣ（Ｏ）Ｒ^２１、ＯＣ（Ｏ）ＯＲ^２１、ＮＯ_２、ＮＨ_２、ＮＨＲ^２１、Ｎ（Ｒ^２１）_２、ＣＨ_２Ｒ^２１、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^２１、Ｃ（Ｏ）Ｎ（Ｒ^２１）_２、ＮＨＣ（Ｏ）Ｒ^２１、ＮＲ^２１Ｃ（Ｏ）Ｒ^２１、Ｃ（Ｏ）ＮＨＯＨ、Ｃ（Ｏ）ＮＨＯＲ^２１、Ｃ（Ｏ）ＮＨＳＯ_２Ｒ^２１、Ｃ（Ｏ）ＮＲ^２１ＳＯ_２Ｒ^２１、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^２１、ＳＯ_２Ｎ（Ｒ^２１）_２、ＣＦ_３、ＣＦ_２ＣＦ_３、Ｃ（Ｏ）Ｈ、Ｃ（Ｏ）ＯＨ、Ｃ（Ｎ）ＮＨ_２、Ｃ（Ｎ）ＮＨＲ^２１、Ｃ（Ｎ）Ｎ（Ｒ^２１）_２、＝ＮＯ−（アルキレン）−Ｃ（Ｏ）ＣＦ_３、ＣＮＯＨ、ＣＮＯＣＨ_３、ＯＨ、（Ｏ）、Ｎ_３、ＣＦ_３、ＣＦ_２ＣＦ_３、ＯＣＦ_３、ＯＣＦ_２ＣＦ_３、Ｆ、Ｃｌ、ＢｒまたはＩで置換されており；
Ｒ^２１は、アルキル、アルケニル、アルキニル、フェニル、ヘテロアリール、シクロアルキル、シクロアルケニルまたは複素環アルキルである。

Where
L ¹ is a bond, alkylene, alkenylene or alkynylene;
A ¹ is C (O) OH or a biological equivalent thereof, or C (O) OR ¹ , C (O) OR ² , C (O) OR ³ or C (O) OR ⁴ ;
¹ , 2, 3, 4 or each of B ¹ , C ¹ , D ¹ , E ¹ and F ¹ are each independently R ¹ , R ² , R ³ or R ⁴ , OR ¹ , SR ¹ , S (O) R ¹ , SO ₂ R ¹ , NH ₂ , NHR ¹ , N (R ¹ ) ₂ , C (O) R ¹ , C (O) NH ₂ , C (O) NHR ¹ , C (O) N (R ¹ ) ₂ , NHC (O) R ¹ , NR ¹ C (O) R ¹ , NHSO ₂ R ¹ , NR ¹ SO ₂ R ¹ , NHC (O) OR ¹ , NR ¹ C (O) OR ¹ , SO ₂ NH ₂ , SO ₂ NHR ¹ , SO ₂ N (R ¹ ) ₂ , NHC (O) NH ₂ , NHC (O) R ¹ NHC (O) N (R ¹ ) ₂ , NR ¹ C (O) N (R ¹ ) ₂ , OR ² , SR ² , S (O) R ² , SO ₂ R ² , NH ₂ , NHR ² , N (R ² ) ₂ , C (O) R ² , C (O) NH ₂ , C (O) NHR ² , C (O) N (R ² ) ₂ , NHC (O) R ² , NR ² C (O) R ² , NHSO ₂ R ² , NR ² SO ₂ R ² , NHC (O) OR ² , NR ² C (O) OR ² , SO ₂ NH ₂ , SO ₂ NHR ² , SO ₂ N (R ² ) ₂ , NHC (O) NH ₂ , NHC (O ) R ² NHC (O) N (R ² ) ₂ , NR ¹ C (O) N (R ² ) ₂ , OR ³ , SR ³ , S (O) R ³ , SO ₂ R ³ , NH ₂ , NHR ³ , N (R ³ ) ₂ , C (O) R ³ , C (O) NH ₂ , C (O) NHR ³ , C (O) N (R ³ ) ₂ , NHC (O) R ³ , NR ² C _{^{(O) R 3, NHSO 2}} R 3, NR 3 SO 2 R 3, NHC (O) OR 3, NR 3 C (O) OR 3, SO 2 NH 2, SO _{^{NHR 3, SO 2 N (R}} 3) 2, NHC (O) NH 2, NHC (O) R 3 NHC (O) N (R 3) 2, NR 1 C (O) N (R 3) 2, OR ⁴ , SR ⁴ , S (O) R ⁴ , SO ₂ R ⁴ , NH ₂ , NHR ⁴ , N (R ⁴ ) ₂ , C (O) R ⁴ , C (O) NH ₂ , C (O) NHR ⁴ , C (O) N (R ⁴ ) ₂ , NHC (O) R ⁴ , NR ⁴ C (O) R ⁴ , NHSO ₂ R ⁴ , NR ⁴ SO ₂ R ⁴ , NHC (O) OR ⁴ , NR ⁴ C (O) OR ⁴ , SO ₂ NH ₂ , SO ₂ NHR ⁴ , SO ₂ N (R ⁴ ) ₂ , NHC (O) NH ₂ , NHC (O) R ⁴ , NHC (O) N (R ⁴ ) ₂ or NR ¹ C (O) N (R ⁴ ) ₂ with the remainder being H, OH, CN, F, Cl, Br or I;
R ¹ is unfused or phenyl fused with benzene, heteroarene or R ^1A ; R ^1A is a cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ² is fused have non or benzene, be heteroarene or R ^2A condensed with heteroaryl; R ^2A is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ³ is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl, each not condensed or condensed with benzene, heteroarene or R ^3A ; R ^3A is cycloalkane, cycloalkene, heterocyclic alkane or A heterocyclic alkene;
R ⁴ is alkyl, alkenyl or alkynyl, each unsubstituted, 1, 2, 3, 4 or 5 independently selected R ⁵ , OR ⁵ , SR ⁵ , S (O) R ⁵ , SO ₂ R ⁵ , NH ₂ , NHR ⁵ , N (R ⁵ ) ₂ , C (O) R ⁵ , C (O) NH ₂ , C (O) NHR ⁵ , C (O) N (R ⁵ ) ₂ , NHC (O) R ⁵ , NR ⁵ C (O) R ⁵ , NHSO ₂ R ⁵ , NR ⁵ SO ₂ R ⁵ , NHC (O) OR ⁵ , NR ⁵ C (O) OR ⁵ , SO ₂ NH ₂ , SO ₂ NHR ⁵ , SO ₂ N (R ⁵ ) ₂ , NHC (O) NH ₂ , NHC (O) R ⁵ , NHC (O) N (R ⁵ ) ₂ , NR ⁵ C (O) N (R ⁵ ) _{2, OH, (O),} C (O) OH, CN, CF 3, OCF 3, CF 2 CF 3, F, Cl, It is substituted with r or I;
R ⁵ is R ⁶ , R ⁷ , R ⁸ or R ⁹ ;
R ⁶ is fused or not benzene is phenyl fused with heteroarene or R ^6A; R ^6A is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ⁷ is fused have non or benzene, be heteroarene or R ^7A condensed with heteroaryl; R ^7A is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ⁸ is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl, each not condensed or fused with benzene, heteroarene or R ^8A ; R ^8A is cycloalkane, cycloalkene, heterocyclic alkane Or a heterocyclic alkene;
R ⁹ is each unsubstituted, 1, 2, 3, 4 or 5 independently selected R ^9A , OR ^9A , SR ^9A , S (O) R ^9A , SO ₂ R ^9A , NH ₂ , NHR ^9A , N (R ^9A ) ₂ , C (O) R ^9A , C (O) NH ₂ , C (O) NHR ^9A , C (O) N (R ^9A ) ₂ , NHC (O) R ^9A , NR ^9A C (O) R ^9A , NHSO ₂ R ^9A , NR ^9A SO ₂ R ^9A , NHC (O) OR ^9A , NR ^9A C (O) OR ^9A , SO ₂ NH ₂ , SO ₂ NHR ^9A , SO ₂ N ( R ^9A ) ₂ , NHC (O) NH ₂ , NHC (O) R ^9A NHC (O) N (R ^9A ) ₂ , NR ^9A C (O) N (R ^9A ) ₂ , OH, (O), C ( _{O) OH, CN, CF 3} , OCF 3, CF 2 CF 3, F, Cl Alkyl substituted by Br or I, alkenyl or alkynyl;
R ^9A is R ^9B , R ^9C or R ^9D ;
R ^9B is phenyl that is unfused or condensed with benzene, heteroarene, or R ^9B2 ; R ^9B2 is a cycloalkane, cycloalkene, heterocyclic alkane, or heterocyclic alkene;
R ^9C is unfused or benzene, be heteroarene or R ^9C2 condensed with heteroaryl; R ^9C2 is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ^9D is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl, each unfused or fused with benzene, heteroarene or R ^9D2 ; R ^9D2 is cycloalkane, cycloalkene, heterocyclic An alkane or a heterocyclic alkene;
Each said cyclic moiety is independently 1 or 2 or 3 or 4 or 5 independently selected R ¹⁰ , OR ¹⁰ , OCH ₂ R ¹⁰ , SR ¹⁰ , S (O) R ¹⁰ , SO ₂ R ¹⁰ , C (O) R ¹⁰ , CO (O) R ¹⁰ , OC (O) R ¹⁰ , OC (O) OR ¹⁰ , NO ₂ , NH ₂ , NHR ¹⁰ , N (R ¹⁰ ) ₂ , CH ₂ R ¹⁰ , C (O) NH ₂ , C (O) NHR ¹⁰ , C (O) N (R ¹⁰ ) ₂ , NHC (O) R ¹⁰ , NR ¹⁰ C (O) R ¹⁰ , C (O) NHOH , C (O) NHOR ¹⁰ , C (O) NHSO ₂ R ¹⁰ , C (O) NR ¹⁰ SO ₂ R ¹⁰ , SO ₂ NH ₂ , SO ₂ NHR ¹⁰ , SO ₂ N (R ¹⁰ ) ₂ , CF ₃ , _{CF 2 CF 3, C (O} ) H, C (O) OH, ^{_{(N) NH 2, C (}} N) NHR 10, C (N) N (R 10) 2, = NO- ( _{alkylene) -C (O) CF 3,} CNOH, CNOCH 3, OH, (O), N ₃ , substituted with CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I;
R ¹⁰ is R ¹¹ , R ¹² , R ¹³ or R ¹⁴ ;
R ¹¹ is unfused or phenyl fused with benzene, heteroarene or R ^11A ; R ^11A is a cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ¹² is fused have non or benzene, be heteroarene or R ^12A condensed with heteroaryl; R ^12A is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ¹³ is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl, each of which is unfused or condensed with benzene, heteroarene or R ^13A ; R ^13A is cycloalkane, cycloalkene, heterocyclic alkane Or a heterocyclic alkene;
R ¹⁴ is each unsubstituted, 1, 2, 3, 4 or 5 independently selected R ¹⁵ , OR ¹⁵ , SR ¹⁵ , S (O) R ¹⁵ , SO ₂ R ¹⁵ , NH ₂ , NHR ¹⁵ , N (R ¹⁵ ) ₂ , C (O) R ¹⁵ , C (O) NH ₂ , C (O) NHR ¹⁵ , C (O) N (R ¹⁵ ) ₂ , NHC (O) R ¹⁵ , NR ¹⁵ C (O) R ¹⁵ , NHSO ₂ R ¹⁵ , NR ¹⁵ SO ₂ R ¹⁵ , NHC (O) OR ¹⁵ , NR ¹⁵ C (O) OR ¹⁵ , SO ₂ NH ₂ , SO ₂ NHR ¹⁵ , SO ₂ N ( R ¹⁵ ) ₂ , NHC (O) NH ₂ , NHC (O) R ¹⁵ , NHC (O) N (R ¹⁵ ) ₂ , NR ¹⁵ C (O) N (R ¹⁵ ) ₂ , OH, (O), C _{(O) OH, CN, CF} 3, OCF 3, CF 2 CF 3, F, l, alkyl substituted by Br or I, alkenyl or alkynyl;
R ¹⁵ is R ¹⁶ , R ¹⁷ , R ¹⁸ or R ¹⁹ ;
R ¹⁶ is fused or not benzene, be heteroarene or R ^15A condensed with phenyl; R ^15A is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ¹⁷ is fused have non or benzene, be heteroarene or R ^16A condensed with heteroaryl; R ^16A is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ¹⁸ is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl, each of which is unfused or fused with benzene, heteroarene or R ^18A ; R ^18A is cycloalkane, cycloalkene, heterocyclic alkane Or a heterocyclic alkene;
R ¹⁹ is alkyl, alkenyl or alkynyl, each unsubstituted or substituted with R ²⁰ ;
R ²⁰ is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclic alkyl;
R ¹¹ , R ¹² , R ¹³ , R ¹⁶ , R ¹⁷ and R ¹⁸ are independently unsubstituted or 1 or 2 or 3 or 4 or 5 independent R ²¹ , OR ²¹ , OCH ₂ R ²¹ , SR ²¹ , S (O) R ²¹ , SO ₂ R ²¹ , C (O) R ²¹ , CO (O) R ²¹ , OC (O) R ²¹ , OC (O) OR ²¹ , NO ₂ , NH ₂ , NHR ²¹ , N (R ²¹ ) ₂ , CH ₂ R ²¹ , C (O) NH ₂ , C (O) NHR ²¹ , C (O) N (R ²¹ ) ₂ , NHC (O) R ²¹ , NR ²¹ C ( O) R ²¹ , C (O) NHOH, C (O) NHOR ²¹ , C (O) NHSO ₂ R ²¹ , C (O) NR ²¹ SO ₂ R ²¹ , SO ₂ NH ₂ , SO ₂ NHR ²¹ , SO _{2 ^{N (R 21) 2, CF}} 3, CF 2 C _{3, C (O) H,} C (O) OH, C (N) NH 2, C (N) NHR 21, C (N) N (R 21) 2, = NO- ( alkylene) -C (O) CF ₃ , CNOH, CNOCH ₃ , OH, (O), N ₃ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I;
R ²¹ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclic alkyl.

  Yet another embodiment relates to a compound having the following formula I and its therapeutically acceptable salts, with or without administration of one or more other therapeutic agents and further with or without radiation therapy. is there.

式中、
Ｌ^１は結合であるか、アルキレン、アルケニレンまたはアルキニレンであり；
Ａ^１はＣ（Ｏ）ＯＨまたはそれの生物学的等価体であるか、Ｃ（Ｏ）ＯＲ^１、Ｃ（Ｏ）ＯＲ^２、Ｃ（Ｏ）ＯＲ^３またはＣ（Ｏ）ＯＲ^４であり；
Ｂ^１、Ｃ^１、Ｄ^１、Ｅ^１およびＦ^１のうちの１、２、３、４個またはそれぞれは独立に、Ｒ^１、Ｒ^２、Ｒ^３もしくはＲ^４、ＯＲ^１、ＳＲ^１、Ｓ（Ｏ）Ｒ^１、ＳＯ_２Ｒ^１、ＮＨ_２、ＮＨＲ^１、Ｎ（Ｒ^１）_２、Ｃ（Ｏ）Ｒ^１、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^１、Ｃ（Ｏ）Ｎ（Ｒ^１）_２、ＮＨＣ（Ｏ）Ｒ^１、ＮＲ^１Ｃ（Ｏ）Ｒ^１、ＮＨＳＯ_２Ｒ^１、ＮＲ^１ＳＯ_２Ｒ^１、ＮＨＣ（Ｏ）ＯＲ^１、ＮＲ^１Ｃ（Ｏ）ＯＲ^１、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^１、ＳＯ_２Ｎ（Ｒ^１）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^１ＮＨＣ（Ｏ）Ｎ（Ｒ^１）_２、ＮＲ^１Ｃ（Ｏ）Ｎ（Ｒ^１）_２、ＯＲ^２、ＳＲ^２、Ｓ（Ｏ）Ｒ^２、ＳＯ_２Ｒ^２、ＮＨ_２、ＮＨＲ^２、Ｎ（Ｒ^２）_２、Ｃ（Ｏ）Ｒ^２、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^２、Ｃ（Ｏ）Ｎ（Ｒ^２）_２、ＮＨＣ（Ｏ）Ｒ^２、ＮＲ^２Ｃ（Ｏ）Ｒ^２、ＮＨＳＯ_２Ｒ^２、ＮＲ^２ＳＯ_２Ｒ^２、ＮＨＣ（Ｏ）ＯＲ^２、ＮＲ^２Ｃ（Ｏ）ＯＲ^２、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^２、ＳＯ_２Ｎ（Ｒ^２）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^２ＮＨＣ（Ｏ）Ｎ（Ｒ^２）_２、ＮＲ^１Ｃ（Ｏ）Ｎ（Ｒ^２）_２、ＯＲ^３、ＳＲ^３、Ｓ（Ｏ）Ｒ^３、ＳＯ_２Ｒ^３、ＮＨ_２、ＮＨＲ^３、Ｎ（Ｒ^３）_２、Ｃ（Ｏ）Ｒ^３、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^３、Ｃ（Ｏ）Ｎ（Ｒ^３）_２、ＮＨＣ（Ｏ）Ｒ^３、ＮＲ^２Ｃ（Ｏ）Ｒ^３、ＮＨＳＯ_２Ｒ^３、ＮＲ^３ＳＯ_２Ｒ^３、ＮＨＣ（Ｏ）ＯＲ^３、ＮＲ^３Ｃ（Ｏ）ＯＲ^３、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^３、ＳＯ_２Ｎ（Ｒ^３）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^３ＮＨＣ（Ｏ）Ｎ（Ｒ^３）_２、ＮＲ^１Ｃ（Ｏ）Ｎ（Ｒ^３）_２、ＯＲ^４、ＳＲ^４、Ｓ（Ｏ）Ｒ^４、ＳＯ_２Ｒ^４、ＮＨ_２、ＮＨＲ^４、Ｎ（Ｒ^４）_２、Ｃ（Ｏ）Ｒ^４、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^４、Ｃ（Ｏ）Ｎ（Ｒ^４）_２、ＮＨＣ（Ｏ）Ｒ^４、ＮＲ^４Ｃ（Ｏ）Ｒ^４、ＮＨＳＯ_２Ｒ^４、ＮＲ^４ＳＯ_２Ｒ^４、ＮＨＣ（Ｏ）ＯＲ^４、ＮＲ^４Ｃ（Ｏ）ＯＲ^４、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^４、ＳＯ_２Ｎ（Ｒ^４）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^４、ＮＨＣ（Ｏ）Ｎ（Ｒ^４）_２またはＮＲ^１Ｃ（Ｏ）Ｎ（Ｒ^４）_２であり、残りのものはＨ、ＯＨ、ＣＮ、Ｆ、Ｃｌ、ＢｒまたはＩであり；
Ｒ^１は、縮合していないかベンゼン、ヘテロアレンまたはＲ^１Ａと縮合しているフェニルであり；Ｒ^１Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^２は、縮合していないかベンゼン、ヘテロアレンまたはＲ^２Ａと縮合しているヘテロアリールであり；Ｒ^２Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^３は、それぞれ縮合していないかベンゼン、ヘテロアレンまたはＲ^３Ａと縮合しているシクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり；Ｒ^３Ａはシクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^４は、アルキル、アルケニルまたはアルキニルであって、それぞれ置換されていないか１、２、３、４もしくは５個の独立に選択されるＲ^５、ＯＲ^５、ＳＲ^５、Ｓ（Ｏ）Ｒ^５、ＳＯ_２Ｒ^５、ＮＨ_２、ＮＨＲ^５、Ｎ（Ｒ^５）_２、Ｃ（Ｏ）Ｒ^５、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^５、Ｃ（Ｏ）Ｎ（Ｒ^５）_２、ＮＨＣ（Ｏ）Ｒ^５、ＮＲ^５Ｃ（Ｏ）Ｒ^５、ＮＨＳＯ_２Ｒ^５、ＮＲ^５ＳＯ_２Ｒ^５、ＮＨＣ（Ｏ）ＯＲ^５、ＮＲ^５Ｃ（Ｏ）ＯＲ^５、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^５、ＳＯ_２Ｎ（Ｒ^５）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^５、ＮＨＣ（Ｏ）Ｎ（Ｒ^５）_２、ＮＲ^５Ｃ（Ｏ）Ｎ（Ｒ^５）_２、ＯＨ、（Ｏ）、Ｃ（Ｏ）ＯＨ、ＣＮ、ＣＦ_３、ＯＣＦ_３、ＣＦ_２ＣＦ_３、Ｆ、Ｃｌ、ＢｒまたはＩで置換されており；
Ｒ^５は、Ｒ^６、Ｒ^７、Ｒ^８またはＲ^９であり；
Ｒ^６は、縮合していないかベンゼン、ヘテロアレンまたはＲ^６Ａと縮合しているフェニルであり；Ｒ^６Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^７は、縮合していないかベンゼン、ヘテロアレンまたはＲ^７Ａと縮合しているヘテロアリールであり；Ｒ^７Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^８は、それぞれ縮合していないかベンゼン、ヘテロアレンまたはＲ^８Ａと縮合しているシクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり；Ｒ^８Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^９は、それぞれ置換されていないか１、２、３、４もしくは５個の独立に選択されるＲ^９Ａ、ＯＲ^９Ａ、ＳＲ^９Ａ、Ｓ（Ｏ）Ｒ^９Ａ、ＳＯ_２Ｒ^９Ａ、ＮＨ_２、ＮＨＲ^９Ａ、Ｎ（Ｒ^９Ａ）_２、Ｃ（Ｏ）Ｒ^９Ａ、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^９Ａ、Ｃ（Ｏ）Ｎ（Ｒ^９Ａ）_２、ＮＨＣ（Ｏ）Ｒ^９Ａ、ＮＲ^９ＡＣ（Ｏ）Ｒ^９Ａ、ＮＨＳＯ_２Ｒ^９Ａ、ＮＲ^９ＡＳＯ_２Ｒ^９Ａ、ＮＨＣ（Ｏ）ＯＲ^９Ａ、ＮＲ^９ＡＣ（Ｏ）ＯＲ^９Ａ、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^９Ａ、ＳＯ_２Ｎ（Ｒ^９Ａ）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^９ＡＮＨＣ（Ｏ）Ｎ（Ｒ^９Ａ）_２、ＮＲ^９ＡＣ（Ｏ）Ｎ（Ｒ^９Ａ）_２、ＯＨ、（Ｏ）、Ｃ（Ｏ）ＯＨ、ＣＮ、ＣＦ_３、ＯＣＦ_３、ＣＦ_２ＣＦ_３、Ｆ、Ｃｌ、ＢｒまたはＩで置換されているアルキル、アルケニルまたはアルキニルであり；
Ｒ^９Ａは、Ｒ^９Ｂ、Ｒ^９ＣまたはＲ^９Ｄであり；
Ｒ^９Ｂは、縮合していないかベンゼン、ヘテロアレンまたはＲ^９Ｂ２と縮合しているフェニルであり；Ｒ^９Ｂ２は、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^９Ｃは、縮合していないかベンゼン、ヘテロアレンまたはＲ^９Ｃ２と縮合しているヘテロアリールであり；Ｒ^９Ｃ２は、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^９Ｄは、それぞれ縮合していないかベンゼン、ヘテロアレンまたはＲ^９Ｄ２と縮合しているシクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり、；Ｒ^９Ｄ２は、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
前記各環状部分は独立に、置換されていないか１もしくは２もしくは３もしくは４もしくは５個の独立に選択されるＲ^１０、ＯＲ^１０、ＯＣＨ_２Ｒ^１０、ＳＲ^１０、Ｓ（Ｏ）Ｒ^１０、ＳＯ_２Ｒ^１０、Ｃ（Ｏ）Ｒ^１０、ＣＯ（Ｏ）Ｒ^１０、ＯＣ（Ｏ）Ｒ^１０、ＯＣ（Ｏ）ＯＲ^１０、ＮＯ_２、ＮＨ_２、ＮＨＲ^１０、Ｎ（Ｒ^１０）_２、ＣＨ_２Ｒ^１０、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^１０、Ｃ（Ｏ）Ｎ（Ｒ^１０）_２、ＮＨＣ（Ｏ）Ｒ^１０、ＮＲ^１０Ｃ（Ｏ）Ｒ^１０、Ｃ（Ｏ）ＮＨＯＨ、Ｃ（Ｏ）ＮＨＯＲ^１０、Ｃ（Ｏ）ＮＨＳＯ_２Ｒ^１０、Ｃ（Ｏ）ＮＲ^１０ＳＯ_２Ｒ^１０、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^１０、ＳＯ_２Ｎ（Ｒ^１０）_２、ＣＦ_３、ＣＦ_２ＣＦ_３、Ｃ（Ｏ）Ｈ、Ｃ（Ｏ）ＯＨ、Ｃ（Ｎ）ＮＨ_２、Ｃ（Ｎ）ＮＨＲ^１０、Ｃ（Ｎ）Ｎ（Ｒ^１０）_２、＝ＮＯ−（アルキレン）−Ｃ（Ｏ）ＣＦ_３、ＣＮＯＨ、ＣＮＯＣＨ_３、ＯＨ、（Ｏ）、Ｎ_３、ＣＦ_３、ＣＦ_２ＣＦ_３、ＯＣＦ_３、ＯＣＦ_２ＣＦ_３、Ｆ、Ｃｌ、ＢｒもしくはＩで置換されており；
Ｒ^１０は、Ｒ^１１、Ｒ^１２、Ｒ^１３またはＲ^１４であり；
Ｒ^１１は、縮合していないかベンゼン、ヘテロアレンまたはＲ^１１Ａと縮合しているフェニルであり；Ｒ^１１Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^１２は、縮合していないかベンゼン、ヘテロアレンまたはＲ^１２Ａと縮合しているヘテロアリールであり；Ｒ^１２Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^１３は、それぞれ縮合していないかベンゼン、ヘテロアレンまたはＲ^１３Ａと縮合しているシクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり；Ｒ^１３Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^１４は、それぞれ置換されていないか１、２、３、４もしくは５個の独立に選択されるＲ^１５、ＯＲ^１５、ＳＲ^１５、Ｓ（Ｏ）Ｒ^１５、ＳＯ_２Ｒ^１５、ＮＨ_２、ＮＨＲ^１５、Ｎ（Ｒ^１５）_２、Ｃ（Ｏ）Ｒ^１５、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^１５、Ｃ（Ｏ）Ｎ（Ｒ^１５）_２、ＮＨＣ（Ｏ）Ｒ^１５、ＮＲ^１５Ｃ（Ｏ）Ｒ^１５、ＮＨＳＯ_２Ｒ^１５、ＮＲ^１５ＳＯ_２Ｒ^１５、ＮＨＣ（Ｏ）ＯＲ^１５、ＮＲ^１５Ｃ（Ｏ）ＯＲ^１５、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^１５、ＳＯ_２Ｎ（Ｒ^１５）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^１５、ＮＨＣ（Ｏ）Ｎ（Ｒ^１５）_２、ＮＲ^１５Ｃ（Ｏ）Ｎ（Ｒ^１５）_２、ＯＨ、（Ｏ）、Ｃ（Ｏ）ＯＨ、ＣＮ、ＣＦ_３、ＯＣＦ_３、ＣＦ_２ＣＦ_３、Ｆ、Ｃｌ、ＢｒまたはＩで置換されているアルキル、アルケニルまたはアルキニルであり；
Ｒ^１５は、Ｒ^１６、Ｒ^１７、Ｒ^１８またはＲ^１９であり；
Ｒ^１６は、縮合していないかベンゼン、ヘテロアレンまたはＲ^１５Ａと縮合しているフェニルであり；Ｒ^１５Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^１７は、縮合していないかベンゼン、ヘテロアレンまたはＲ^１６Ａと縮合しているヘテロアリールであり；Ｒ^１６Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^１８は、それぞれ縮合していないかベンゼン、ヘテロアレンまたはＲ^１８Ａと縮合しているシクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり；Ｒ^１８Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^１９は、それぞれ置換されていないかＲ^２０で置換されているアルキル、アルケニルまたはアルキニルであり；
Ｒ^２０は、フェニル、ヘテロアリール、シクロアルキル、シクロアルケニルまたは複素環アルキルであり；
Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｒ^１６、Ｒ^１７およびＲ^１８は独立に、置換されていないか１もしくは２もしくは３もしくは４もしくは５個の独立のＲ^２１、ＯＲ^２１、ＯＣＨ_２Ｒ^２１、ＳＲ^２１、Ｓ（Ｏ）Ｒ^２１、ＳＯ_２Ｒ^２１、Ｃ（Ｏ）Ｒ^２１、ＣＯ（Ｏ）Ｒ^２１、ＯＣ（Ｏ）Ｒ^２１、ＯＣ（Ｏ）ＯＲ^２１、ＮＯ_２、ＮＨ_２、ＮＨＲ^２１、Ｎ（Ｒ^２１）_２、ＣＨ_２Ｒ^２１、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^２１、Ｃ（Ｏ）Ｎ（Ｒ^２１）_２、ＮＨＣ（Ｏ）Ｒ^２１、ＮＲ^２１Ｃ（Ｏ）Ｒ^２１、Ｃ（Ｏ）ＮＨＯＨ、Ｃ（Ｏ）ＮＨＯＲ^２１、Ｃ（Ｏ）ＮＨＳＯ_２Ｒ^２１、Ｃ（Ｏ）ＮＲ^２１ＳＯ_２Ｒ^２１、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^２１、ＳＯ_２Ｎ（Ｒ^２１）_２、ＣＦ_３、ＣＦ_２ＣＦ_３、Ｃ（Ｏ）Ｈ、Ｃ（Ｏ）ＯＨ、Ｃ（Ｎ）ＮＨ_２、Ｃ（Ｎ）ＮＨＲ^２１、Ｃ（Ｎ）Ｎ（Ｒ^２１）_２、＝ＮＯ−（アルキレン）−Ｃ（Ｏ）ＣＦ_３、ＣＮＯＨ、ＣＮＯＣＨ_３、ＯＨ、（Ｏ）、Ｎ_３、ＣＦ_３、ＣＦ_２ＣＦ_３、ＯＣＦ_３、ＯＣＦ_２ＣＦ_３、Ｆ、Ｃｌ、ＢｒまたはＩで置換されており；
Ｒ^２１は、アルキル、アルケニル、アルキニル、フェニル、ヘテロアリール、シクロアルキル、シクロアルケニルまたは複素環アルキルである。

Where
L ¹ is a bond, alkylene, alkenylene or alkynylene;
A ¹ is C (O) OH or a biological equivalent thereof, or C (O) OR ¹ , C (O) OR ² , C (O) OR ³ or C (O) OR ⁴ ;
¹ , 2, 3, 4 or each of B ¹ , C ¹ , D ¹ , E ¹ and F ¹ are each independently R ¹ , R ² , R ³ or R ⁴ , OR ¹ , SR ¹ , S (O) R ¹ , SO ₂ R ¹ , NH ₂ , NHR ¹ , N (R ¹ ) ₂ , C (O) R ¹ , C (O) NH ₂ , C (O) NHR ¹ , C (O) N (R ¹ ) ₂ , NHC (O) R ¹ , NR ¹ C (O) R ¹ , NHSO ₂ R ¹ , NR ¹ SO ₂ R ¹ , NHC (O) OR ¹ , NR ¹ C (O) OR ¹ , SO ₂ NH ₂ , SO ₂ NHR ¹ , SO ₂ N (R ¹ ) ₂ , NHC (O) NH ₂ , NHC (O) R ¹ NHC (O) N (R ¹ ) ₂ , NR ¹ C (O) N (R ¹ ) ₂ , OR ² , SR ² , S (O) R ² , SO ₂ R ² , NH ₂ , NHR ² , N (R ² ) ₂ , C (O) R ² , C (O) NH ₂ , C (O) NHR ² , C (O) N (R ² ) ₂ , NHC (O) R ² , NR ² C (O) R ² , NHSO ₂ R ² , NR ² SO ₂ R ² , NHC (O) OR ² , NR ² C (O) OR ² , SO ₂ NH ₂ , SO ₂ NHR ² , SO ₂ N (R ² ) ₂ , NHC (O) NH ₂ , NHC (O ) R ² NHC (O) N (R ² ) ₂ , NR ¹ C (O) N (R ² ) ₂ , OR ³ , SR ³ , S (O) R ³ , SO ₂ R ³ , NH ₂ , NHR ³ , N (R ³ ) ₂ , C (O) R ³ , C (O) NH ₂ , C (O) NHR ³ , C (O) N (R ³ ) ₂ , NHC (O) R ³ , NR ² C _{^{(O) R 3, NHSO 2}} R 3, NR 3 SO 2 R 3, NHC (O) OR 3, NR 3 C (O) OR 3, SO 2 NH 2, SO _{^{NHR 3, SO 2 N (R}} 3) 2, NHC (O) NH 2, NHC (O) R 3 NHC (O) N (R 3) 2, NR 1 C (O) N (R 3) 2, OR ⁴ , SR ⁴ , S (O) R ⁴ , SO ₂ R ⁴ , NH ₂ , NHR ⁴ , N (R ⁴ ) ₂ , C (O) R ⁴ , C (O) NH ₂ , C (O) NHR ⁴ , C (O) N (R ⁴ ) ₂ , NHC (O) R ⁴ , NR ⁴ C (O) R ⁴ , NHSO ₂ R ⁴ , NR ⁴ SO ₂ R ⁴ , NHC (O) OR ⁴ , NR ⁴ C (O) OR ⁴ , SO ₂ NH ₂ , SO ₂ NHR ⁴ , SO ₂ N (R ⁴ ) ₂ , NHC (O) NH ₂ , NHC (O) R ⁴ , NHC (O) N (R ⁴ ) ₂ or NR ¹ C (O) N (R ⁴ ) ₂ with the remainder being H, OH, CN, F, Cl, Br or I;
R ¹ is unfused or phenyl fused with benzene, heteroarene or R ^1A ; R ^1A is a cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ² is fused have non or benzene, be heteroarene or R ^2A condensed with heteroaryl; R ^2A is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ³ is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl, each not condensed or condensed with benzene, heteroarene or R ^3A ; R ^3A is cycloalkane, cycloalkene, heterocyclic alkane or A heterocyclic alkene;
R ⁴ is alkyl, alkenyl or alkynyl, each unsubstituted, 1, 2, 3, 4 or 5 independently selected R ⁵ , OR ⁵ , SR ⁵ , S (O) R ⁵ , SO ₂ R ⁵ , NH ₂ , NHR ⁵ , N (R ⁵ ) ₂ , C (O) R ⁵ , C (O) NH ₂ , C (O) NHR ⁵ , C (O) N (R ⁵ ) ₂ , NHC (O) R ⁵ , NR ⁵ C (O) R ⁵ , NHSO ₂ R ⁵ , NR ⁵ SO ₂ R ⁵ , NHC (O) OR ⁵ , NR ⁵ C (O) OR ⁵ , SO ₂ NH ₂ , SO ₂ NHR ⁵ , SO ₂ N (R ⁵ ) ₂ , NHC (O) NH ₂ , NHC (O) R ⁵ , NHC (O) N (R ⁵ ) ₂ , NR ⁵ C (O) N (R ⁵ ) _{2, OH, (O),} C (O) OH, CN, CF 3, OCF 3, CF 2 CF 3, F, Cl, It is substituted with r or I;
R ⁵ is R ⁶ , R ⁷ , R ⁸ or R ⁹ ;
R ⁶ is fused or not benzene is phenyl fused with heteroarene or R ^6A; R ^6A is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ⁷ is fused have non or benzene, be heteroarene or R ^7A condensed with heteroaryl; R ^7A is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ⁸ is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl, each not condensed or fused with benzene, heteroarene or R ^8A ; R ^8A is cycloalkane, cycloalkene, heterocyclic alkane Or a heterocyclic alkene;
R ⁹ is each unsubstituted, 1, 2, 3, 4 or 5 independently selected R ^9A , OR ^9A , SR ^9A , S (O) R ^9A , SO ₂ R ^9A , NH ₂ , NHR ^9A , N (R ^9A ) ₂ , C (O) R ^9A , C (O) NH ₂ , C (O) NHR ^9A , C (O) N (R ^9A ) ₂ , NHC (O) R ^9A , NR ⁹ AC (O) R ^9A , NHSO ₂ R ^9A , NR ^9A SO ₂ R ^9A , NHC (O) OR ^9A , NR ^9A C (O) OR ^9A , SO ₂ NH ₂ , SO ₂ NHR ^9A , SO ₂ N ( R ^9A ) ₂ , NHC (O) NH ₂ , NHC (O) R ^9A NHC (O) N (R ^9A ) ₂ , NR ^9A C (O) N (R ^9A ) ₂ , OH, (O), C ( _{O) OH, CN, CF 3} , OCF 3, CF 2 CF 3, F, Cl Alkyl substituted by Br or I, alkenyl or alkynyl;
R ^9A is R ^9B , R ^9C or R ^9D ;
R ^9B is phenyl that is unfused or condensed with benzene, heteroarene, or R ^9B2 ; R ^9B2 is a cycloalkane, cycloalkene, heterocyclic alkane, or heterocyclic alkene;
R ^9C is unfused or benzene, be heteroarene or R ^9C2 condensed with heteroaryl; R ^9C2 is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ^9D is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl, each unfused or fused with benzene, heteroarene or R ^9D2 ; R ^9D2 is cycloalkane, cycloalkene, heterocyclic An alkane or a heterocyclic alkene;
Each said cyclic moiety is independently 1 or 2 or 3 or 4 or 5 independently selected R ¹⁰ , OR ¹⁰ , OCH ₂ R ¹⁰ , SR ¹⁰ , S (O) R ¹⁰ , SO ₂ R ¹⁰ , C (O) R ¹⁰ , CO (O) R ¹⁰ , OC (O) R ¹⁰ , OC (O) OR ¹⁰ , NO ₂ , NH ₂ , NHR ¹⁰ , N (R ¹⁰ ) ₂ , CH ₂ R ¹⁰ , C (O) NH ₂ , C (O) NHR ¹⁰ , C (O) N (R ¹⁰ ) ₂ , NHC (O) R ¹⁰ , NR ¹⁰ C (O) R ¹⁰ , C (O) NHOH , C (O) NHOR ¹⁰ , C (O) NHSO ₂ R ¹⁰ , C (O) NR ¹⁰ SO ₂ R ¹⁰ , SO ₂ NH ₂ , SO ₂ NHR ¹⁰ , SO ₂ N (R ¹⁰ ) ₂ , CF ₃ , _{CF 2 CF 3, C (O} ) H, C (O) OH, ^{_{(N) NH 2, C (}} N) NHR 10, C (N) N (R 10) 2, = NO- ( _{alkylene) -C (O) CF 3,} CNOH, CNOCH 3, OH, (O), N ₃ , substituted with CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I;
R ¹⁰ is R ¹¹ , R ¹² , R ¹³ or R ¹⁴ ;
R ¹¹ is unfused or phenyl fused with benzene, heteroarene or R ^11A ; R ^11A is a cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ¹² is fused have non or benzene, be heteroarene or R ^12A condensed with heteroaryl; R ^12A is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ¹³ is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl, each of which is unfused or condensed with benzene, heteroarene or R ^13A ; R ^13A is cycloalkane, cycloalkene, heterocyclic alkane Or a heterocyclic alkene;
R ¹⁴ is each unsubstituted, 1, 2, 3, 4 or 5 independently selected R ¹⁵ , OR ¹⁵ , SR ¹⁵ , S (O) R ¹⁵ , SO ₂ R ¹⁵ , NH ₂ , NHR ¹⁵ , N (R ¹⁵ ) ₂ , C (O) R ¹⁵ , C (O) NH ₂ , C (O) NHR ¹⁵ , C (O) N (R ¹⁵ ) ₂ , NHC (O) R ¹⁵ , NR ¹⁵ C (O) R ¹⁵ , NHSO ₂ R ¹⁵ , NR ¹⁵ SO ₂ R ¹⁵ , NHC (O) OR ¹⁵ , NR ¹⁵ C (O) OR ¹⁵ , SO ₂ NH ₂ , SO ₂ NHR ¹⁵ , SO ₂ N ( R ¹⁵ ) ₂ , NHC (O) NH ₂ , NHC (O) R ¹⁵ , NHC (O) N (R ¹⁵ ) ₂ , NR ¹⁵ C (O) N (R ¹⁵ ) ₂ , OH, (O), C _{(O) OH, CN, CF} 3, OCF 3, CF 2 CF 3, F, l, alkyl substituted by Br or I, alkenyl or alkynyl;
R ¹⁵ is R ¹⁶ , R ¹⁷ , R ¹⁸ or R ¹⁹ ;
R ¹⁶ is fused or not benzene, be heteroarene or R ^15A condensed with phenyl; R ^15A is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ¹⁷ is fused have non or benzene, be heteroarene or R ^16A condensed with heteroaryl; R ^16A is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ¹⁸ is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl, each of which is unfused or fused with benzene, heteroarene or R ^18A ; R ^18A is cycloalkane, cycloalkene, heterocyclic alkane Or a heterocyclic alkene;
R ¹⁹ is alkyl, alkenyl or alkynyl, each unsubstituted or substituted with R ²⁰ ;
R ²⁰ is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclic alkyl;
R ¹¹ , R ¹² , R ¹³ , R ¹⁶ , R ¹⁷ and R ¹⁸ are independently unsubstituted or 1 or 2 or 3 or 4 or 5 independent R ²¹ , OR ²¹ , OCH ₂ R ²¹ , SR ²¹ , S (O) R ²¹ , SO ₂ R ²¹ , C (O) R ²¹ , CO (O) R ²¹ , OC (O) R ²¹ , OC (O) OR ²¹ , NO ₂ , NH ₂ , NHR ²¹ , N (R ²¹ ) ₂ , CH ₂ R ²¹ , C (O) NH ₂ , C (O) NHR ²¹ , C (O) N (R ²¹ ) ₂ , NHC (O) R ²¹ , NR ²¹ C ( O) R ²¹ , C (O) NHOH, C (O) NHOR ²¹ , C (O) NHSO ₂ R ²¹ , C (O) NR ²¹ SO ₂ R ²¹ , SO ₂ NH ₂ , SO ₂ NHR ²¹ , SO _{2 ^{N (R 21) 2, CF}} 3, CF 2 C _{3, C (O) H,} C (O) OH, C (N) NH 2, C (N) NHR 21, C (N) N (R 21) 2, = NO- ( alkylene) -C (O) CF ₃ , CNOH, CNOCH ₃ , OH, (O), N ₃ , CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , F, Cl, Br or I;
R ²¹ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclic alkyl.

  Yet another embodiment relates to compounds having the following Formula I and therapeutically acceptable salts thereof:

式中、
Ｌ^１は結合であるか、アルキレン、アルケニレンまたはアルキニレンであり；
Ａ^１はＣ（Ｏ）ＯＨまたはそれの生物学的等価体であるか、Ｃ（Ｏ）ＯＲ^１、Ｃ（Ｏ）ＯＲ^２、Ｃ（Ｏ）ＯＲ^３またはＣ（Ｏ）ＯＲ^４であり；
Ｂ^１、Ｃ^１、Ｄ^１、Ｅ^１およびＦ^１のうちの１、２、３、４個またはそれぞれは独立に、Ｒ^１、Ｒ^２、Ｒ^３もしくはＲ^４、ＯＲ^１、ＳＲ^１、Ｓ（Ｏ）Ｒ^１、ＳＯ_２Ｒ^１、ＮＨ_２、ＮＨＲ^１、Ｎ（Ｒ^１）_２、Ｃ（Ｏ）Ｒ^１、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^１、Ｃ（Ｏ）Ｎ（Ｒ^１）_２、ＮＨＣ（Ｏ）Ｒ^１、ＮＲ^１Ｃ（Ｏ）Ｒ^１、ＮＨＳＯ_２Ｒ^１、ＮＲ^１ＳＯ_２Ｒ^１、ＮＨＣ（Ｏ）ＯＲ^１、ＮＲ^１Ｃ（Ｏ）ＯＲ^１、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^１、ＳＯ_２Ｎ（Ｒ^１）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^１ＮＨＣ（Ｏ）Ｎ（Ｒ^１）_２、ＮＲ^１Ｃ（Ｏ）Ｎ（Ｒ^１）_２、ＯＲ^２、ＳＲ^２、Ｓ（Ｏ）Ｒ^２、ＳＯ_２Ｒ^２、ＮＨ_２、ＮＨＲ^２、Ｎ（Ｒ^２）_２、Ｃ（Ｏ）Ｒ^２、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^２、Ｃ（Ｏ）Ｎ（Ｒ^２）_２、ＮＨＣ（Ｏ）Ｒ^２、ＮＲ^２Ｃ（Ｏ）Ｒ^２、ＮＨＳＯ_２Ｒ^２、ＮＲ^２ＳＯ_２Ｒ^２、ＮＨＣ（Ｏ）ＯＲ^２、ＮＲ^２Ｃ（Ｏ）ＯＲ^２、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^２、ＳＯ_２Ｎ（Ｒ^２）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^２ＮＨＣ（Ｏ）Ｎ（Ｒ^２）_２、ＮＲ^１Ｃ（Ｏ）Ｎ（Ｒ^２）_２、ＯＲ^３、ＳＲ^３、Ｓ（Ｏ）Ｒ^３、ＳＯ_２Ｒ^３、ＮＨ_２、ＮＨＲ^３、Ｎ（Ｒ^３）_２、Ｃ（Ｏ）Ｒ^３、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^３、Ｃ（Ｏ）Ｎ（Ｒ^３）_２、ＮＨＣ（Ｏ）Ｒ^３、ＮＲ^２Ｃ（Ｏ）Ｒ^３、ＮＨＳＯ_２Ｒ^３、ＮＲ^３ＳＯ_２Ｒ^３、ＮＨＣ（Ｏ）ＯＲ^３、ＮＲ^３Ｃ（Ｏ）ＯＲ^３、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^３、ＳＯ_２Ｎ（Ｒ^３）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^３ＮＨＣ（Ｏ）Ｎ（Ｒ^３）_２、ＮＲ^１Ｃ（Ｏ）Ｎ（Ｒ^３）_２、ＯＲ^４、ＳＲ^４、Ｓ（Ｏ）Ｒ^４、ＳＯ_２Ｒ^４、ＮＨ_２、ＮＨＲ^４、Ｎ（Ｒ^４）_２、Ｃ（Ｏ）Ｒ^４、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^４、Ｃ（Ｏ）Ｎ（Ｒ^４）_２、ＮＨＣ（Ｏ）Ｒ^４、ＮＲ^４Ｃ（Ｏ）Ｒ^４、ＮＨＳＯ_２Ｒ^４、ＮＲ^４ＳＯ_２Ｒ^４、ＮＨＣ（Ｏ）ＯＲ^４、ＮＲ^４Ｃ（Ｏ）ＯＲ^４、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^４、ＳＯ_２Ｎ（Ｒ^４）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^４、ＮＨＣ（Ｏ）Ｎ（Ｒ^４）_２またはＮＲ^１Ｃ（Ｏ）Ｎ（Ｒ^４）_２であり、残りのものはＨ、ＯＨ、ＣＮ、Ｆ、Ｃｌ、ＢｒまたはＩであり；
Ｒ^１は、縮合していないかベンゼン、ヘテロアレンまたはＲ^１Ａと縮合しているフェニルであり；Ｒ^１Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^２は、縮合していないかベンゼン、ヘテロアレンまたはＲ^２Ａと縮合しているヘテロアリールであり；Ｒ^２Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^３は、それぞれ縮合していないかベンゼン、ヘテロアレンまたはＲ^３Ａと縮合しているシクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり；Ｒ^３Ａはシクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^４は、アルキル、アルケニルまたはアルキニルであって、それぞれ置換されていないか１、２、３、４もしくは５個の独立に選択されるＲ^５、ＯＲ^５、ＳＲ^５、Ｓ（Ｏ）Ｒ^５、ＳＯ_２Ｒ^５、ＮＨ_２、ＮＨＲ^５、Ｎ（Ｒ^５）_２、Ｃ（Ｏ）Ｒ^５、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^５、Ｃ（Ｏ）Ｎ（Ｒ^５）_２、ＮＨＣ（Ｏ）Ｒ^５、ＮＲ^５Ｃ（Ｏ）Ｒ^５、ＮＨＳＯ_２Ｒ^５、ＮＲ^５ＳＯ_２Ｒ^５、ＮＨＣ（Ｏ）ＯＲ^５、ＮＲ^５Ｃ（Ｏ）ＯＲ^５、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^５、ＳＯ_２Ｎ（Ｒ^５）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^５、ＮＨＣ（Ｏ）Ｎ（Ｒ^５）_２、ＮＲ^５Ｃ（Ｏ）Ｎ（Ｒ^５）_２、ＯＨ、（Ｏ）、Ｃ（Ｏ）ＯＨ、ＣＮ、ＣＦ_３、ＯＣＦ_３、ＣＦ_２ＣＦ_３、Ｆ、Ｃｌ、ＢｒまたはＩで置換されており；
Ｒ^５は、Ｒ^６、Ｒ^７、Ｒ^８またはＲ^９であり；
Ｒ^６は、縮合していないかベンゼン、ヘテロアレンまたはＲ^６Ａと縮合しているフェニルであり；Ｒ^６Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^７は、縮合していないかベンゼン、ヘテロアレンまたはＲ^７Ａと縮合しているヘテロアリールであり；Ｒ^７Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^８は、それぞれ縮合していないかベンゼン、ヘテロアレンまたはＲ^８Ａと縮合しているシクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり；Ｒ^８Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^９は、それぞれ置換されていないか１、２、３、４もしくは５個の独立に選択されるＲ^９Ａ、ＯＲ^９Ａ、ＳＲ^９Ａ、Ｓ（Ｏ）Ｒ^９Ａ、ＳＯ_２Ｒ^９Ａ、ＮＨ_２、ＮＨＲ^９Ａ、Ｎ（Ｒ^９Ａ）_２、Ｃ（Ｏ）Ｒ^９Ａ、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^９Ａ、Ｃ（Ｏ）Ｎ（Ｒ^９Ａ）_２、ＮＨＣ（Ｏ）Ｒ^９Ａ、ＮＲ^９ＡＣ（Ｏ）Ｒ^９Ａ、ＮＨＳＯ_２Ｒ^９Ａ、ＮＲ^９ＡＳＯ_２Ｒ^９Ａ、ＮＨＣ（Ｏ）ＯＲ^９Ａ、ＮＲ^９ＡＣ（Ｏ）ＯＲ^９Ａ、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^９Ａ、ＳＯ_２Ｎ（Ｒ^９Ａ）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^９ＡＮＨＣ（Ｏ）Ｎ（Ｒ^９Ａ）_２、ＮＲ^９ＡＣ（Ｏ）Ｎ（Ｒ^９Ａ）_２、ＯＨ、（Ｏ）、Ｃ（Ｏ）ＯＨ、ＣＮ、ＣＦ_３、ＯＣＦ_３、ＣＦ_２ＣＦ_３、Ｆ、Ｃｌ、ＢｒまたはＩで置換されているアルキル、アルケニルまたはアルキニルであり；
Ｒ^９Ａは、Ｒ^９Ｂ、Ｒ^９ＣまたはＲ^９Ｄであり；
Ｒ^９Ｂは、縮合していないかベンゼン、ヘテロアレンまたはＲ^９Ｂ２と縮合しているフェニルであり；Ｒ^９Ｂ２は、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^９Ｃは、縮合していないかベンゼン、ヘテロアレンまたはＲ^９Ｃ２と縮合しているヘテロアリールであり；Ｒ^９Ｃ２は、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^９Ｄは、それぞれ縮合していないかベンゼン、ヘテロアレンまたはＲ^９Ｄ２と縮合しているシクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり；Ｒ^９Ｄ２は、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
前記各環状部分は独立に、置換されていないか１もしくは２もしくは３個の独立に選択されるＲ^１０、ＯＲ^１０、Ｃ（Ｏ）Ｒ^１０、ＮＯ_２、Ｎ（Ｒ^１０）_２、Ｃ（Ｏ）ＮＨＲ^１０、ＳＯ_２Ｎ（Ｒ^１０）_２、Ｃ（Ｏ）ＯＨ、ＯＨ、（Ｏ）、ＣＦ_３、ＯＣＦ_３、Ｆ、Ｃｌ、ＢｒもしくはＩで置換されており；
Ｒ^１０は、Ｒ^１１、Ｒ^１２、Ｒ^１３またはＲ^１４であり；
Ｒ^１１は、縮合していないかベンゼン、ヘテロアレンまたはＲ^１１Ａと縮合しているフェニルであり；Ｒ^１１Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^１２は、縮合していないかベンゼン、ヘテロアレンまたはＲ^１２Ａと縮合しているヘテロアリールであり；Ｒ^１２Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^１３は、それぞれ縮合していないかベンゼン、ヘテロアレンまたはＲ^１３Ａと縮合しているシクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり；Ｒ^１３Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^１４は、それぞれ置換されていないか１、２、３、４もしくは５個の独立に選択されるＲ^１５、ＯＲ^１５、ＳＲ^１５、Ｓ（Ｏ）Ｒ^１５、ＳＯ_２Ｒ^１５、ＮＨ_２、ＮＨＲ^１５、Ｎ（Ｒ^１５）_２、Ｃ（Ｏ）Ｒ^１５、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^１５、Ｃ（Ｏ）Ｎ（Ｒ^１５）_２、ＮＨＣ（Ｏ）Ｒ^１５、ＮＲ^１５Ｃ（Ｏ）Ｒ^１５、ＮＨＳＯ_２Ｒ^１５、ＮＲ^１５ＳＯ_２Ｒ^１５、ＮＨＣ（Ｏ）ＯＲ^１５、ＮＲ^１５Ｃ（Ｏ）ＯＲ^１５、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^１５、ＳＯ_２Ｎ（Ｒ^１５）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^１５、ＮＨＣ（Ｏ）Ｎ（Ｒ^１５）_２、ＮＲ^１５Ｃ（Ｏ）Ｎ（Ｒ^１５）_２、ＯＨ、（Ｏ）、Ｃ（Ｏ）ＯＨ、ＣＮ、ＣＦ_３、ＯＣＦ_３、ＣＦ_２ＣＦ_３、Ｆ、Ｃｌ、ＢｒまたはＩで置換されているアルキル、アルケニルまたはアルキニルであり；
Ｒ^１５は、Ｒ^１６、Ｒ^１７、Ｒ^１８またはＲ^１９であり；
Ｒ^１６は、縮合していないかベンゼン、ヘテロアレンまたはＲ^１５Ａと縮合しているフェニルであり；Ｒ^１５Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^１７は、縮合していないかベンゼン、ヘテロアレンまたはＲ^１６Ａと縮合しているヘテロアリールであり；Ｒ^１６Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^１８は、それぞれ縮合していないかベンゼン、ヘテロアレンまたはＲ^１８Ａと縮合しているシクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり；Ｒ^１８Ａは、シクロアルカン、シクロアルケン、複素環アルカンまたは複素環アルケンであり；
Ｒ^１９は、それぞれ置換されていないかＲ^２０で置換されているアルキル、アルケニルまたはアルキニルであり；
Ｒ^２０は、フェニル、ヘテロアリール、シクロアルキル、シクロアルケニルまたは複素環アルキルであり；
Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｒ^１６、Ｒ^１７およびＲ^１８は独立に、置換されていないか１もしくは２もしくは３もしくは４もしくは５個の独立のＯＲ^２１、ＮＯ_２、ＣＦ_３、Ｆ、Ｃｌ、ＢｒまたはＩで置換されており；
Ｒ^２１は、アルキル、アルケニル、アルキニル、フェニル、ヘテロアリール、シクロアルキル、シクロアルケニルまたは複素環アルキルである。

Where
L ¹ is a bond, alkylene, alkenylene or alkynylene;
A ¹ is C (O) OH or a biological equivalent thereof, or C (O) OR ¹ , C (O) OR ² , C (O) OR ³ or C (O) OR ⁴ ;
¹ , 2, 3, 4 or each of B ¹ , C ¹ , D ¹ , E ¹ and F ¹ are each independently R ¹ , R ² , R ³ or R ⁴ , OR ¹ , SR ¹ , S (O) R ¹ , SO ₂ R ¹ , NH ₂ , NHR ¹ , N (R ¹ ) ₂ , C (O) R ¹ , C (O) NH ₂ , C (O) NHR ¹ , C (O) N (R ¹ ) ₂ , NHC (O) R ¹ , NR ¹ C (O) R ¹ , NHSO ₂ R ¹ , NR ¹ SO ₂ R ¹ , NHC (O) OR ¹ , NR ¹ C (O) OR ¹ , SO ₂ NH ₂ , SO ₂ NHR ¹ , SO ₂ N (R ¹ ) ₂ , NHC (O) NH ₂ , NHC (O) R ¹ NHC (O) N (R ¹ ) ₂ , NR ¹ C (O) N (R ¹ ) ₂ , OR ² , SR ² , S (O) R ² , SO ₂ R ² , NH ₂ , NHR ² , N (R ² ) ₂ , C (O) R ² , C (O) NH ₂ , C (O) NHR ² , C (O) N (R ² ) ₂ , NHC (O) R ² , NR ² C (O) R ² , NHSO ₂ R ² , NR ² SO ₂ R ² , NHC (O) OR ² , NR ² C (O) OR ² , SO ₂ NH ₂ , SO ₂ NHR ² , SO ₂ N (R ² ) ₂ , NHC (O) NH ₂ , NHC (O ) R ² NHC (O) N (R ² ) ₂ , NR ¹ C (O) N (R ² ) ₂ , OR ³ , SR ³ , S (O) R ³ , SO ₂ R ³ , NH ₂ , NHR ³ , N (R ³ ) ₂ , C (O) R ³ , C (O) NH ₂ , C (O) NHR ³ , C (O) N (R ³ ) ₂ , NHC (O) R ³ , NR ² C _{^{(O) R 3, NHSO 2}} R 3, NR 3 SO 2 R 3, NHC (O) OR 3, NR 3 C (O) OR 3, SO 2 NH 2, SO _{^{NHR 3, SO 2 N (R}} 3) 2, NHC (O) NH 2, NHC (O) R 3 NHC (O) N (R 3) 2, NR 1 C (O) N (R 3) 2, OR ⁴ , SR ⁴ , S (O) R ⁴ , SO ₂ R ⁴ , NH ₂ , NHR ⁴ , N (R ⁴ ) ₂ , C (O) R ⁴ , C (O) NH ₂ , C (O) NHR ⁴ , C (O) N (R ⁴ ) ₂ , NHC (O) R ⁴ , NR ⁴ C (O) R ⁴ , NHSO ₂ R ⁴ , NR ⁴ SO ₂ R ⁴ , NHC (O) OR ⁴ , NR ⁴ C (O) OR ⁴ , SO ₂ NH ₂ , SO ₂ NHR ⁴ , SO ₂ N (R ⁴ ) ₂ , NHC (O) NH ₂ , NHC (O) R ⁴ , NHC (O) N (R ⁴ ) ₂ or NR ¹ C (O) N (R ⁴ ) ₂ with the remainder being H, OH, CN, F, Cl, Br or I;
R ¹ is unfused or phenyl fused with benzene, heteroarene or R ^1A ; R ^1A is a cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ² is fused have non or benzene, be heteroarene or R ^2A condensed with heteroaryl; R ^2A is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ³ is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl, each not condensed or condensed with benzene, heteroarene or R ^3A ; R ^3A is cycloalkane, cycloalkene, heterocyclic alkane or A heterocyclic alkene;
R ⁴ is alkyl, alkenyl or alkynyl, each unsubstituted, 1, 2, 3, 4 or 5 independently selected R ⁵ , OR ⁵ , SR ⁵ , S (O) R ⁵ , SO ₂ R ⁵ , NH ₂ , NHR ⁵ , N (R ⁵ ) ₂ , C (O) R ⁵ , C (O) NH ₂ , C (O) NHR ⁵ , C (O) N (R ⁵ ) ₂ , NHC (O) R ⁵ , NR ⁵ C (O) R ⁵ , NHSO ₂ R ⁵ , NR ⁵ SO ₂ R ⁵ , NHC (O) OR ⁵ , NR ⁵ C (O) OR ⁵ , SO ₂ NH ₂ , SO ₂ NHR ⁵ , SO ₂ N (R ⁵ ) ₂ , NHC (O) NH ₂ , NHC (O) R ⁵ , NHC (O) N (R ⁵ ) ₂ , NR ⁵ C (O) N (R ⁵ ) _{2, OH, (O),} C (O) OH, CN, CF 3, OCF 3, CF 2 CF 3, F, Cl, It is substituted with r or I;
R ⁵ is R ⁶ , R ⁷ , R ⁸ or R ⁹ ;
R ⁶ is fused or not benzene is phenyl fused with heteroarene or R ^6A; R ^6A is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ⁷ is fused have non or benzene, be heteroarene or R ^7A condensed with heteroaryl; R ^7A is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ⁸ is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl, each not condensed or fused with benzene, heteroarene or R ^8A ; R ^8A is cycloalkane, cycloalkene, heterocyclic alkane Or a heterocyclic alkene;
R ⁹ is each unsubstituted, 1, 2, 3, 4 or 5 independently selected R ^9A , OR ^9A , SR ^9A , S (O) R ^9A , SO ₂ R ^9A , NH ₂ , NHR ^9A , N (R ^9A ) ₂ , C (O) R ^9A , C (O) NH ₂ , C (O) NHR ^9A , C (O) N (R ^9A ) ₂ , NHC (O) R ^9A , NR ^9A C (O) R ^9A , NHSO ₂ R ^9A , NR ^9A SO ₂ R ^9A , NHC (O) OR ^9A , NR ^9A C (O) OR ^9A , SO ₂ NH ₂ , SO ₂ NHR ^9A , SO ₂ N ( R ^9A ) ₂ , NHC (O) NH ₂ , NHC (O) R ^9A NHC (O) N (R ^9A ) ₂ , NR ^9A C (O) N (R ^9A ) ₂ , OH, (O), C ( _{O) OH, CN, CF 3} , OCF 3, CF 2 CF 3, F, Cl Alkyl substituted by Br or I, alkenyl or alkynyl;
R ^9A is R ^9B , R ^9C or R ^9D ;
R ^9B is phenyl that is unfused or condensed with benzene, heteroarene, or R ^9B2 ; R ^9B2 is a cycloalkane, cycloalkene, heterocyclic alkane, or heterocyclic alkene;
R ^9C is unfused or benzene, be heteroarene or R ^9C2 condensed with heteroaryl; R ^9C2 is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ^9D is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl, each of which is not condensed or condensed with benzene, heteroarene or R ^9D2 ; R ^9D2 is cycloalkane, cycloalkene, heterocyclic alkane Or a heterocyclic alkene;
Each said cyclic moiety is independently unsubstituted or 1 or 2 or 3 independently selected R ¹⁰ , OR ¹⁰ , C (O) R ¹⁰ , NO ₂ , N (R ¹⁰ ) ₂ , C ( O) NHR ¹⁰ , SO ₂ N (R ¹⁰ ) ₂ , C (O) OH, OH, (O), CF ₃ , OCF ₃ , F, Cl, Br or I;
R ¹⁰ is R ¹¹ , R ¹² , R ¹³ or R ¹⁴ ;
R ¹¹ is unfused or phenyl fused with benzene, heteroarene or R ^11A ; R ^11A is a cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ¹² is fused have non or benzene, be heteroarene or R ^12A condensed with heteroaryl; R ^12A is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ¹³ is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl, each of which is unfused or condensed with benzene, heteroarene or R ^13A ; R ^13A is cycloalkane, cycloalkene, heterocyclic alkane Or a heterocyclic alkene;
R ¹⁴ is each unsubstituted, 1, 2, 3, 4 or 5 independently selected R ¹⁵ , OR ¹⁵ , SR ¹⁵ , S (O) R ¹⁵ , SO ₂ R ¹⁵ , NH ₂ , NHR ¹⁵ , N (R ¹⁵ ) ₂ , C (O) R ¹⁵ , C (O) NH ₂ , C (O) NHR ¹⁵ , C (O) N (R ¹⁵ ) ₂ , NHC (O) R ¹⁵ , NR ¹⁵ C (O) R ¹⁵ , NHSO ₂ R ¹⁵ , NR ¹⁵ SO ₂ R ¹⁵ , NHC (O) OR ¹⁵ , NR ¹⁵ C (O) OR ¹⁵ , SO ₂ NH ₂ , SO ₂ NHR ¹⁵ , SO ₂ N ( R ¹⁵ ) ₂ , NHC (O) NH ₂ , NHC (O) R ¹⁵ , NHC (O) N (R ¹⁵ ) ₂ , NR ¹⁵ C (O) N (R ¹⁵ ) ₂ , OH, (O), C _{(O) OH, CN, CF} 3, OCF 3, CF 2 CF 3, F, l, alkyl substituted by Br or I, alkenyl or alkynyl;
R ¹⁵ is R ¹⁶ , R ¹⁷ , R ¹⁸ or R ¹⁹ ;
R ¹⁶ is fused or not benzene, be heteroarene or R ^15A condensed with phenyl; R ^15A is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ¹⁷ is fused have non or benzene, be heteroarene or R ^16A condensed with heteroaryl; R ^16A is an cycloalkane, cycloalkene, heterocyclic alkane or heterocyclic alkene;
R ¹⁸ is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl, each of which is unfused or fused with benzene, heteroarene or R ^18A ; R ^18A is cycloalkane, cycloalkene, heterocyclic alkane Or a heterocyclic alkene;
R ¹⁹ is alkyl, alkenyl or alkynyl, each unsubstituted or substituted with R ²⁰ ;
R ²⁰ is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclic alkyl;
R ¹¹ , R ¹² , R ¹³ , R ¹⁶ , R ¹⁷ and R ¹⁸ are independently unsubstituted or 1 or 2 or 3 or 4 or 5 independent OR ²¹ , NO ₂ , CF ₃ , F, Substituted with Cl, Br or I;
R ²¹ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclic alkyl.

  Yet another embodiment relates to compounds having the following Formula I and therapeutically acceptable salts thereof:

式中、
Ｌ^１は結合であるか、アルキレン、アルケニレンまたはアルキニレンであり；
Ａ^１はＣ（Ｏ）ＯＨまたはそれの生物学的等価体であるか、Ｃ（Ｏ）ＯＲ^１、Ｃ（Ｏ）ＯＲ^２、Ｃ（Ｏ）ＯＲ^３またはＣ（Ｏ）ＯＲ^４であり；
Ｂ^１、Ｃ^１、Ｄ^１、Ｅ^１およびＦ^１のうちの１、２、３、４個またはそれぞれは独立に、Ｒ^１、Ｒ^２、Ｒ^３もしくはＲ^４、ＯＲ^１、ＳＲ^１、Ｓ（Ｏ）Ｒ^１、ＳＯ_２Ｒ^１、ＮＨ_２、ＮＨＲ^１、Ｎ（Ｒ^１）_２、Ｃ（Ｏ）Ｒ^１、Ｃ（Ｏ）ＮＨ_２、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^１、ＳＯ_２Ｎ（Ｒ^１）_２、ＯＲ^２、ＳＲ^２、Ｓ（Ｏ）Ｒ^２、ＳＯ_２Ｒ^２、ＮＨ_２、ＮＨＲ^２、Ｎ（Ｒ^２）_２、Ｃ（Ｏ）Ｒ^２、Ｃ（Ｏ）ＮＨ_２、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^２、ＳＯ_２Ｎ（Ｒ^２）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＯＲ^３、ＳＲ^３、Ｓ（Ｏ）Ｒ^３、ＳＯ_２Ｒ^３、ＮＨ_２、ＮＨＲ^３、Ｎ（Ｒ^３）_２、Ｃ（Ｏ）Ｒ^３、Ｃ（Ｏ）ＮＨ_２、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^３、ＳＯ_２Ｎ（Ｒ^３）_２、ＯＲ^４、ＳＲ^４、Ｓ（Ｏ）Ｒ^４、ＳＯ_２Ｒ^４、ＮＨ_２、ＮＨＲ^４、Ｎ（Ｒ^４）_２、Ｃ（Ｏ）Ｒ^４、Ｃ（Ｏ）ＮＨ_２、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^４またはＳＯ_２Ｎ（Ｒ^４）_２であり、残りのものはＨ、ＯＨ、ＣＮ、Ｆ、Ｃｌ、ＢｒまたはＩであり；
Ｒ^１は、縮合していないかベンゼンと縮合しているフェニルであり；
Ｒ^２は、ヘテロアリールであり；
Ｒ^３は、シクロアルキル、シクロアルケニルまたは複素環アルキルであり；
Ｒ^４は、アルキル、アルケニルまたはアルキニルであって、それぞれ置換されていないか１、２、３、４もしくは５個の独立に選択されるＲ^５、ＯＲ^５、ＳＲ^５、Ｓ（Ｏ）Ｒ^５、ＳＯ_２Ｒ^５、ＮＨ_２、ＮＨＲ^５、Ｎ（Ｒ^５）_２、Ｃ（Ｏ）Ｒ^５、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^５、Ｃ（Ｏ）Ｎ（Ｒ^５）_２、ＮＨＣ（Ｏ）Ｒ^５、ＮＲ^５Ｃ（Ｏ）Ｒ^５、ＮＨＳＯ_２Ｒ^５、ＮＲ^５ＳＯ_２Ｒ^５、ＮＨＣ（Ｏ）ＯＲ^５、ＮＲ^５Ｃ（Ｏ）ＯＲ^５、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^５、ＳＯ_２Ｎ（Ｒ^５）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^５、ＮＨＣ（Ｏ）Ｎ（Ｒ^５）_２、ＮＲ^５Ｃ（Ｏ）Ｎ（Ｒ^５）_２、ＯＨ、（Ｏ）、Ｃ（Ｏ）ＯＨ、ＣＮ、ＣＦ_３、ＯＣＦ_３、ＣＦ_２ＣＦ_３、Ｆ、Ｃｌ、ＢｒまたはＩで置換されており；
Ｒ^５は、Ｒ^６、Ｒ^７、Ｒ^８またはＲ^９であり；
Ｒ^６は、縮合していないかベンゼン、ヘテロアレンまたはＲ^６Ａと縮合しているフェニルであり；Ｒ^６Ａは、シクロアルカンであり；
Ｒ^７は、ヘテロアリールであり；
Ｒ^８は、シクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり；
Ｒ^９は、それぞれ置換されていないか１、２、３、４もしくは５個の独立に選択されるＲ^９Ａ、ＯＲ^９Ａ、ＳＲ^９Ａ、Ｓ（Ｏ）Ｒ^９Ａ、ＳＯ_２Ｒ^９Ａ、ＮＨ_２、ＮＨＲ^９Ａ、Ｎ（Ｒ^９Ａ）_２、Ｃ（Ｏ）Ｒ^９Ａ、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^９Ａ、Ｃ（Ｏ）Ｎ（Ｒ^９Ａ）_２、ＮＨＣ（Ｏ）Ｒ^９Ａ、ＮＲ^９ＡＣ（Ｏ）Ｒ^９Ａ、ＮＨＳＯ_２Ｒ^９Ａ、ＮＲ^９ＡＳＯ_２Ｒ^９Ａ、ＮＨＣ（Ｏ）ＯＲ^９Ａ、ＮＲ^９ＡＣ（Ｏ）ＯＲ^９Ａ、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^９Ａ、ＳＯ_２Ｎ（Ｒ^９Ａ）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^９ＡＮＨＣ（Ｏ）Ｎ（Ｒ^９Ａ）_２、ＮＲ^９ＡＣ（Ｏ）Ｎ（Ｒ^９Ａ）_２、ＯＨ、（Ｏ）、Ｃ（Ｏ）ＯＨ、ＣＮ、ＣＦ_３、ＯＣＦ_３、ＣＦ_２ＣＦ_３、Ｆ、Ｃｌ、ＢｒまたはＩで置換されているアルキル、アルケニルまたはアルキニルであり；
Ｒ^９Ａは、Ｒ^９Ｂ、Ｒ^９ＣまたはＲ^９Ｄであり；
Ｒ^９Ｂは、フェニルであり；
Ｒ^９Ｃは、ヘテロアリールであり；
Ｒ^９Ｄは、シクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり；
前記各環状部分は独立に、置換されていないか１もしくは２もしくは３個の独立に選択されるＲ^１０、ＯＲ^１０、Ｃ（Ｏ）Ｒ^１０、ＮＯ_２、Ｎ（Ｒ^１０）_２、Ｃ（Ｏ）ＮＨＲ^１０、ＳＯ_２Ｎ（Ｒ^１０）_２、Ｃ（Ｏ）ＯＨ、ＯＨ、（Ｏ）、ＣＦ_３、ＯＣＦ_３、Ｆ、Ｃｌ、ＢｒもしくはＩで置換されており；
Ｒ^１０は、Ｒ^１１、Ｒ^１２、Ｒ^１３またはＲ^１４であり；
Ｒ^１１は、縮合していないかベンゼンと縮合しているフェニルであり；
Ｒ^１２は、ヘテロアリールであり；
Ｒ^１３は、シクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり；
Ｒ^１４は、それぞれ置換されていないか１、２、３、４もしくは５個の独立に選択されるＲ^１５、ＯＲ^１５、ＳＲ^１５、Ｓ（Ｏ）Ｒ^１５、ＳＯ_２Ｒ^１５、ＮＨ_２、ＮＨＲ^１５、Ｎ（Ｒ^１５）_２、Ｃ（Ｏ）Ｒ^１５、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^１５、Ｃ（Ｏ）Ｎ（Ｒ^１５）_２、ＮＨＣ（Ｏ）Ｒ^１５、ＮＲ^１５Ｃ（Ｏ）Ｒ^１５、ＮＨＳＯ_２Ｒ^１５、ＮＲ^１５ＳＯ_２Ｒ^１５、ＮＨＣ（Ｏ）ＯＲ^１５、ＮＲ^１５Ｃ（Ｏ）ＯＲ^１５、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＲ^１５、ＳＯ_２Ｎ（Ｒ^１５）_２、ＮＨＣ（Ｏ）ＮＨ_２、ＮＨＣ（Ｏ）Ｒ^１５、ＮＨＣ（Ｏ）Ｎ（Ｒ^１５）_２、ＮＲ^１５Ｃ（Ｏ）Ｎ（Ｒ^１５）_２、ＯＨ、（Ｏ）、Ｃ（Ｏ）ＯＨ、ＣＮ、ＣＦ_３、ＯＣＦ_３、ＣＦ_２ＣＦ_３、Ｆ、Ｃｌ、ＢｒまたはＩで置換されているアルキル、アルケニルまたはアルキニルであり；
Ｒ^１５は、Ｒ^１６、Ｒ^１７、Ｒ^１８またはＲ^１９であり；
Ｒ^１６は、フェニルであり；
Ｒ^１７は、ヘテロアリールであり；
Ｒ^１８は、シクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり；
Ｒ^１９は、それぞれ置換されていないかＲ^２０で置換されているアルキル、アルケニルまたはアルキニルであり；
Ｒ^２０は、フェニル、ヘテロアリール、シクロアルキル、シクロアルケニルまたは複素環アルキルであり；
Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｒ^１６、Ｒ^１７およびＲ^１８は独立に、置換されていないか１もしくは２もしくは３もしくは４もしくは５個の独立のＯＲ^２１、ＮＯ_２、ＣＦ_３、Ｆ、Ｃｌ、ＢｒまたはＩで置換されており；
Ｒ^２１は、アルキル、アルケニル、アルキニル、フェニル、ヘテロアリール、シクロアルキル、シクロアルケニルまたは複素環アルキルである。

Where
L ¹ is a bond, alkylene, alkenylene or alkynylene;
A ¹ is C (O) OH or a biological equivalent thereof, or C (O) OR ¹ , C (O) OR ² , C (O) OR ³ or C (O) OR ⁴ ;
¹ , 2, 3, 4 or each of B ¹ , C ¹ , D ¹ , E ¹ and F ¹ are each independently R ¹ , R ² , R ³ or R ⁴ , OR ¹ , SR ¹ , S (O) R ¹ , SO ₂ R ¹ , NH ₂ , NHR ¹ , N (R ¹ ) ₂ , C (O) R ¹ , C (O) NH ₂ , SO ₂ NH ₂ , SO ₂ NHR ¹ , SO ₂ N (R ¹ ) ₂ , OR ² , SR ² , S (O) R ² , SO ₂ R ² , NH ₂ , NHR ² , N (R ² ) ₂ , C (O) R ² , C (O) NH ₂ , SO ₂ NH ₂ , SO ₂ NHR ² , SO ₂ N (R ² ) ₂ , NHC (O) NH ₂ , OR ³ , SR ³ , S (O) R ³ , SO ₂ R ³ , NH ₂ , NHR _{^{3, N (R 3) 2}} , C (O) R 3, C (O) NH 2, SO 2 NH 2, SO 2 NHR 3, SO 2 N (R _{^{) 2, OR 4, SR 4}} , S (O) R 4, SO 2 R 4, NH 2, NHR 4, N (R 4) 2, C (O) R 4, C (O) NH 2, SO 2 NH ₂ , SO ₂ NHR ⁴ or SO ₂ N (R ⁴ ) ₂ with the remainder being H, OH, CN, F, Cl, Br or I;
R ¹ is phenyl that is not condensed or condensed with benzene;
R ² is heteroaryl;
R ³ is cycloalkyl, cycloalkenyl or heterocyclic alkyl;
R ⁴ is alkyl, alkenyl or alkynyl, each unsubstituted, 1, 2, 3, 4 or 5 independently selected R ⁵ , OR ⁵ , SR ⁵ , S (O) R ⁵ , SO ₂ R ⁵ , NH ₂ , NHR ⁵ , N (R ⁵ ) ₂ , C (O) R ⁵ , C (O) NH ₂ , C (O) NHR ⁵ , C (O) N (R ⁵ ) ₂ , NHC (O) R ⁵ , NR ⁵ C (O) R ⁵ , NHSO ₂ R ⁵ , NR ⁵ SO ₂ R ⁵ , NHC (O) OR ⁵ , NR ⁵ C (O) OR ⁵ , SO ₂ NH ₂ , SO ₂ NHR ⁵ , SO ₂ N (R ⁵ ) ₂ , NHC (O) NH ₂ , NHC (O) R ⁵ , NHC (O) N (R ⁵ ) ₂ , NR ⁵ C (O) N (R ⁵ ) _{2, OH, (O),} C (O) OH, CN, CF 3, OCF 3, CF 2 CF 3, F, Cl, It is substituted with r or I;
R ⁵ is R ⁶ , R ⁷ , R ⁸ or R ⁹ ;
R ⁶ is unfused or phenyl fused with benzene, heteroarene or R ^6A ; R ^6A is a cycloalkane;
R ⁷ is heteroaryl;
R ⁸ is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl;
R ⁹ is each unsubstituted, 1, 2, 3, 4 or 5 independently selected R ^9A , OR ^9A , SR ^9A , S (O) R ^9A , SO ₂ R ^9A , NH ₂ , NHR ^9A , N (R ^9A ) ₂ , C (O) R ^9A , C (O) NH ₂ , C (O) NHR ^9A , C (O) N (R ^9A ) ₂ , NHC (O) R ^9A , NR ^9A C (O) R ^9A , NHSO ₂ R ^9A , NR ^9A SO ₂ R ^9A , NHC (O) OR ^9A , NR ^9A C (O) OR ^9A , SO ₂ NH ₂ , SO ₂ NHR ^9A , SO ₂ N ( R ^9A ) ₂ , NHC (O) NH ₂ , NHC (O) R ^9A NHC (O) N (R ^9A ) ₂ , NR ^9A C (O) N (R ^9A ) ₂ , OH, (O), C ( _{O) OH, CN, CF 3} , OCF 3, CF 2 CF 3, F, Cl Alkyl substituted by Br or I, alkenyl or alkynyl;
R ^9A is R ^9B , R ^9C or R ^9D ;
R ^9B is phenyl;
R ^9C is heteroaryl;
R ^9D is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl;
Each said cyclic moiety is independently unsubstituted or 1 or 2 or 3 independently selected R ¹⁰ , OR ¹⁰ , C (O) R ¹⁰ , NO ₂ , N (R ¹⁰ ) ₂ , C ( O) NHR ¹⁰ , SO ₂ N (R ¹⁰ ) ₂ , C (O) OH, OH, (O), CF ₃ , OCF ₃ , F, Cl, Br or I;
R ¹⁰ is R ¹¹ , R ¹² , R ¹³ or R ¹⁴ ;
R ¹¹ is phenyl that is not condensed or condensed with benzene;
R ¹² is heteroaryl;
R ¹³ is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl;
R ¹⁴ is each unsubstituted, 1, 2, 3, 4 or 5 independently selected R ¹⁵ , OR ¹⁵ , SR ¹⁵ , S (O) R ¹⁵ , SO ₂ R ¹⁵ , NH ₂ , NHR ¹⁵ , N (R ¹⁵ ) ₂ , C (O) R ¹⁵ , C (O) NH ₂ , C (O) NHR ¹⁵ , C (O) N (R ¹⁵ ) ₂ , NHC (O) R ¹⁵ , NR ¹⁵ C (O) R ¹⁵ , NHSO ₂ R ¹⁵ , NR ¹⁵ SO ₂ R ¹⁵ , NHC (O) OR ¹⁵ , NR ¹⁵ C (O) OR ¹⁵ , SO ₂ NH ₂ , SO ₂ NHR ¹⁵ , SO ₂ N ( R ¹⁵ ) ₂ , NHC (O) NH ₂ , NHC (O) R ¹⁵ , NHC (O) N (R ¹⁵ ) ₂ , NR ¹⁵ C (O) N (R ¹⁵ ) ₂ , OH, (O), C _{(O) OH, CN, CF} 3, OCF 3, CF 2 CF 3, F, l, alkyl substituted by Br or I, alkenyl or alkynyl;
R ¹⁵ is R ¹⁶ , R ¹⁷ , R ¹⁸ or R ¹⁹ ;
R ¹⁶ is phenyl;
R ¹⁷ is heteroaryl;
R ¹⁸ is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl;
R ¹⁹ is alkyl, alkenyl or alkynyl, each unsubstituted or substituted with R ²⁰ ;
R ²⁰ is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclic alkyl;
R ¹¹ , R ¹² , R ¹³ , R ¹⁶ , R ¹⁷ and R ¹⁸ are independently unsubstituted or 1 or 2 or 3 or 4 or 5 independent OR ²¹ , NO ₂ , CF ₃ , F, Substituted with Cl, Br or I;
R ²¹ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclic alkyl.

  Yet another embodiment relates to compounds having the following Formula I and therapeutically acceptable salts thereof:

式中、
Ｌ^１は結合であり；
Ａ^１はＣ（Ｏ）ＯＨであり；
Ｂ^１、Ｃ^１、Ｄ^１、Ｅ^１およびＦ^１のうちの１、２、３、４個またはそれぞれは独立に、Ｒ^１、Ｒ^２、Ｒ^３もしくはＲ^４、ＮＨＲ^１ＯＲ^４であり、残りのものはＨ、ＯＨ、ＣＮ、Ｆ、Ｃｌ、ＢｒまたはＩであり；
Ｒ^１は、縮合していないかベンゼンと縮合しているフェニルであり；
Ｒ^２は、ヘテロアリールであり；
Ｒ^３は、シクロアルキル、シクロアルケニルまたは複素環アルキルであり；
Ｒ^４は、アルキル、アルケニルまたはアルキニルであって、それぞれ置換されていないか１、２、３、４もしくは５個の独立に選択されるＲ^５、ＯＲ^５、ＳＲ^５、ＮＨ_２、ＮＨＲ^５、Ｎ（Ｒ^５）_２、Ｃ（Ｏ）Ｒ^５、ＮＨＣ（Ｏ）Ｒ^５、Ｆ、Ｃｌ、ＢｒまたはＩで置換されており；
Ｒ^５は、Ｒ^６、Ｒ^７、Ｒ^８またはＲ^９であり；
Ｒ^６は、縮合していないかベンゼン、ヘテロアレンまたはＲ^６Ａと縮合しているフェニルであり；Ｒ^６Ａは、シクロアルカンであり；
Ｒ^７は、ヘテロアリールであり；
Ｒ^８は、シクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり；
Ｒ^９は、それぞれ置換されていないか１、２、３、４もしくは５個の独立に選択されるＲ^９Ａ、Ｆ、Ｃｌ、ＢｒまたはＩで置換されているアルキル、アルケニルまたはアルキニルであり；
Ｒ^９Ａは、Ｒ^９Ｂ、Ｒ^９ＣまたはＲ^９Ｄであり；
Ｒ^９Ｂは、フェニルであり；
Ｒ^９Ｃは、ヘテロアリールであり；
Ｒ^９Ｄは、シクロアルキルであり；
前記各環状部分は独立に、置換されていないか１もしくは２もしくは３個の独立に選択されるＲ^１０、ＯＲ^１０、Ｃ（Ｏ）Ｒ^１０、ＮＯ_２、Ｎ（Ｒ^１０）_２、Ｃ（Ｏ）ＮＨＲ^１０、ＳＯ_２Ｎ（Ｒ^１０）_２、Ｃ（Ｏ）ＯＨ、ＯＨ、（Ｏ）、ＣＦ_３、ＯＣＦ_３、Ｆ、Ｃｌ、ＢｒもしくはＩで置換されており；
Ｒ^１０は、Ｒ^１１、Ｒ^１３またはＲ^１４であり；
Ｒ^１１は、縮合していないかベンゼンと縮合しているフェニルであり；
Ｒ^１３は、シクロアルキル、シクロアルケニル、複素環アルキルまたは複素環アルケニルであり；
Ｒ^１４は、それぞれ置換されていないか１、２、３、４もしくは５個の独立に選択されるＲ^１５、ＯＲ^１５、ＳＯ_２Ｒ^１５、Ｎ（Ｒ^１５）_２、Ｆ、Ｃｌ、ＢｒまたはＩで置換されているアルキルまたはアルケニルであり；
Ｒ^１５は、Ｒ^１６、Ｒ^１８またはＲ^１９であり；
Ｒ^１６は、フェニルであり；
Ｒ^１８は、複素環アルキルであり；
Ｒ^１９は、アルキルであり；
Ｒ^１１およびＲ^１６は独立に、置換されていないか１もしくは２もしくは３もしくは４もしくは５個の独立のＯＲ^２１、ＮＯ_２、ＣＦ_３、Ｆ、Ｃｌ、ＢｒまたはＩで置換されており；
Ｒ^２１は、アルキルである。

Where
L ¹ is a bond;
A ¹ is C (O) OH;
¹ , 2, 3, 4 or each of B ¹ , C ¹ , D ¹ , E ¹ and F ¹ are each independently R ¹ , R ² , R ³ or R ⁴ , NHR ¹ OR ⁴ ; The rest are H, OH, CN, F, Cl, Br or I;
R ¹ is phenyl that is not condensed or condensed with benzene;
R ² is heteroaryl;
R ³ is cycloalkyl, cycloalkenyl or heterocyclic alkyl;
R ⁴ is alkyl, alkenyl or alkynyl, each unsubstituted, 1, 2, 3, 4 or 5 independently selected R ⁵ , OR ⁵ , SR ⁵ , NH ₂ , NHR ⁵ , Substituted with N (R ⁵ ) ₂ , C (O) R ⁵ , NHC (O) R ⁵ , F, Cl, Br or I;
R ⁵ is R ⁶ , R ⁷ , R ⁸ or R ⁹ ;
R ⁶ is unfused or phenyl fused with benzene, heteroarene or R ^6A ; R ^6A is a cycloalkane;
R ⁷ is heteroaryl;
R ⁸ is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl;
R ⁹ is alkyl, alkenyl or alkynyl, each unsubstituted or substituted with 1, 2, 3, 4 or 5 independently selected R ^9A , F, Cl, Br or I;
R ^9A is R ^9B , R ^9C or R ^9D ;
R ^9B is phenyl;
R ^9C is heteroaryl;
R ^9D is cycloalkyl;
Each said cyclic moiety is independently unsubstituted or 1 or 2 or 3 independently selected R ¹⁰ , OR ¹⁰ , C (O) R ¹⁰ , NO ₂ , N (R ¹⁰ ) ₂ , C ( O) NHR ¹⁰ , SO ₂ N (R ¹⁰ ) ₂ , C (O) OH, OH, (O), CF ₃ , OCF ₃ , F, Cl, Br or I;
R ¹⁰ is R ¹¹ , R ¹³ or R ¹⁴ ;
R ¹¹ is phenyl that is not condensed or condensed with benzene;
R ¹³ is cycloalkyl, cycloalkenyl, heterocyclic alkyl or heterocyclic alkenyl;
R ¹⁴ is each unsubstituted, 1, 2, 3, 4 or 5 independently selected R ¹⁵ , OR ¹⁵ , SO ₂ R ¹⁵ , N (R ¹⁵ ) ₂ , F, Cl, Br or Alkyl or alkenyl substituted with I;
R ¹⁵ is R ¹⁶ , R ¹⁸ or R ¹⁹ ;
R ¹⁶ is phenyl;
R ¹⁸ is heterocyclic alkyl;
R ¹⁹ is alkyl;
R ¹¹ and R ¹⁶ are independently unsubstituted or substituted with 1 or 2 or 3 or 4 or 5 independent OR ²¹ , NO ₂ , CF ₃ , F, Cl, Br or I;
R ²¹ is alkyl.

Yet another embodiment is
3- (3-cyclohexylpropyl) -1H-indole-2-carboxylic acid;
3- (4-cyclohexylbutyl) -1H-indole-2-carboxylic acid;
3- (3- (3-chlorophenoxy) propyl) -1H-indole-2-carboxylic acid;
3- (3- (3- (trifluoromethyl) phenoxy) propyl) -1H-indole-2-carboxylic acid;
3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3- (2-benzylphenoxy) propyl) -1H-indole-2-carboxylic acid;
3- (3- (2,3-dihydro-1H-inden-5-yloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3-((3-methyl-1-naphthyl) oxy) propyl) -1H-indole-2-carboxylic acid;
3- (3-((2-methyl-1-naphthyl) oxy) propyl) -1H-indole-2-carboxylic acid;
3- (3- (1-naphthylthio) propyl) -1H-indole-2-carboxylic acid;
5-bromo-3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3- (1-naphthyloxy) propyl) -5-((1E) -3-phenylprop-1-enyl) -1H-indole-2-carboxylic acid;
5-((E) -2-cyclohexylvinyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3- (1-naphthyloxy) propyl) -5-((E) -2-phenylvinyl) -1H-indole-2-carboxylic acid;
5- (4-fluorophenyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3- (1-naphthyloxy) propyl) -5- (2-phenylethyl) -1H-indole-2-carboxylic acid;
3- (3-((7-methyl-2,3-dihydro-1H-inden-4-yl) oxy) propyl) -1H-indole-2-carboxylic acid;
3- (3- (5,6,7,8-tetrahydronaphthalen-1-yloxy) propyl) -1H-indole-2-carboxylic acid;
4- (4-fluorophenyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3- (1-naphthyloxy) propyl) -6-((E) -2-phenylvinyl) -1H-indole-2-carboxylic acid;
3- (3- (1-naphthyloxy) propyl) -6-((1E) -3-phenylprop-1-enyl) -1H-indole-2-carboxylic acid;
3- (3- (1-naphthyloxy) propyl) -4-((1E) -3-phenylprop-1-enyl) -1H-indole-2-carboxylic acid;
6- (3- (benzyloxy) phenyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
4- (3- (benzyloxy) phenyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
5-bromo-3- (4- (1-naphthyloxy) butyl) -1H-indole-2-carboxylic acid;
1-methyl-3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3- (1-naphthyloxy) propyl) -6-phenyl-1H-indole-2-carboxylic acid;
6- (2-methylphenyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
6- (3-methylphenyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
6- (4-methylphenyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (1-naphthyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3-(((3- (dimethylamino) propyl) amino) carbonyl) phenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (1,1′-biphenyl-2-yl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (2-methylphenyl) -1- (3- (2-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (2-methylphenyl) -1- (3- (5,6,7,8-tetrahydronaphthalen-1-yloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3-chlorophenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1- (3- (1-naphthyloxy) propyl) -3-phenyl-1H-indole-2-carboxylic acid;
1- (3- (1-naphthyloxy) propyl) -3- (2- (trifluoromethyl) phenyl) -1H-indole-2-carboxylic acid;
1- (3- (1-naphthyloxy) propyl) -3- (3- (trifluoromethyl) phenyl) -1H-indole-2-carboxylic acid;
1- (3- (1-naphthyloxy) propyl) -3- (4- (trifluoromethyl) phenyl) -1H-indole-2-carboxylic acid;
1- (3- (1-naphthyloxy) propyl) -3- (4- (trifluoromethoxy) phenyl) -1H-indole-2-carboxylic acid;
3- (2,3-dimethylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (2,5-dimethylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3,4-dimethylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3,5-dimethylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (2,5-dimethoxyphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3,4-dimethoxyphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (2-methylphenyl) -1- (4- (1-naphthyloxy) butyl) -1H-indole-2-carboxylic acid;
3- (2-methylphenyl) -1- (4- (2-naphthyloxy) butyl) -1H-indole-2-carboxylic acid;
1- (4- (2,3-dichlorophenoxy) butyl) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid;
1- (2- (2,4-dichlorophenoxy) ethyl) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid;
1- (3- (2,4-dichlorophenoxy) propyl) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid;
1- (4- (2,4-dichlorophenoxy) butyl) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid;
3-benzyl-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (2-methylbenzyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3-methylbenzyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (4-methylbenzyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (2-naphthylmethyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1- (3- (1-naphthyloxy) propyl) -3- (2-phenylethyl) -1H-indole-2-carboxylic acid;
1- (3- (1-naphthyloxy) propyl) -3- (3-phenylpropyl) -1H-indole-2-carboxylic acid;
3- (2-methylphenyl) -1- (2- (1-naphthyloxy) ethyl) -1H-indole-2-carboxylic acid;
3- (2-methylphenyl) -1- (2- (2-naphthyloxy) ethyl) -1H-indole-2-carboxylic acid;
1- (2- (2,3-dichlorophenoxy) ethyl) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid;
1- (3- (1-naphthyloxy) propyl) -3-((E) -2-phenylvinyl) -1H-indole-2-carboxylic acid;
1- (3- (1-naphthyloxy) propyl) -3-((1E) -3-phenylprop-1-enyl) -1H-indole-2-carboxylic acid;
3-((E) -2-cyclohexylvinyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1- (3- (1-naphthyloxy) propyl) -3- (3- (piperidin-1-ylcarbonyl) phenyl) -1H-indole-2carboxylic acid;
3- (4-fluoro-3- (morpholin-4-ylcarbonyl) phenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3-(((2-methoxyethyl) amino) carbonyl) phenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3-((dimethylamino) sulfonyl) phenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3- (morpholin-4-ylmethyl) phenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1- (3- (1-naphthyloxy) propyl) -3-piperidin-1-yl-1H-indole-2-carboxylic acid;
3-morpholin-4-yl-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1- (3- (1-naphthyloxy) propyl) -3-((3- (trifluoromethoxy) phenyl) amino) -1H-indole-2-carboxylic acid;
3- (4-carboxypiperidin-1-yl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3-anilino-4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3- (1-naphthylthio) cyclohexyl) -1H-indole-2-carboxylic acid;
3- (3- (1-naphthyloxy) cyclohexyl) -1H-indole-2-carboxylic acid;
1- (2-methylbenzyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1- (2- (dimethylamino) ethyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1- (3-methylbenzyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1- (4-methylbenzyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1- (1,1′-biphenyl-2-ylmethyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1- (1,1′-biphenyl-3-ylmethyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1- (1,1′-biphenyl-4-ylmethyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1- (2,4-dimethylbenzyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1- (4-carboxybenzyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1-((2S) -2-methyl-3- (1-naphthyloxy) propyl) -4- (2-methylphenyl) -1H-indole-2-carboxylic acid;
1-((2R) -2-methyl-3- (1-naphthyloxy) propyl) -4- (2-methylphenyl) -1H-indole-2-carboxylic acid;
3- (3- (1-naphthyloxy) propyl) -1- (pyridin-4-ylmethyl) -1H-indole-2-carboxylic acid;
3- (3- (1-naphthyloxy) propyl) -1- (pyridin-2-ylmethyl) -1H-indole-2-carboxylic acid;
1- (4-methoxybenzyl) -3- (2- (1-naphthyloxy) ethoxy) -1H-indole-2-carboxylic acid;
1- (4-methoxybenzyl) -3- (3- (1-naphthyloxy) prop-1-inyl) -1H-indole-2-carboxylic acid;
4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
4- (2,6-dimethylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1- (3- (1-naphthyloxy) propyl) -4- (1,3,5-trimethyl-1H-pyrazol-4-yl) -1H-indole-2-carboxylic acid;
1- (3- (1-naphthyloxy) propyl) -4- (2-oxocyclohexyl) -1H-indole-2-carboxylic acid;
4- (2-methylphenyl) -3- (morpholin-4-ylmethyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -3- (pyrrolidin-1-ylmethyl) -1H-indole-2-carboxylic acid;
3-((dimethylamino) methyl) -4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3-((((cyclohexylmethyl) amino) methyl) -4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
4- (2-morpholin-4-ylcyclohexyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
4- (2-methylphenyl) -3-((4-methylpiperazin-1-yl) methyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -3- (piperidin-1-ylmethyl) -1H-indole-2-carboxylic acid;
4- (2-methylphenyl) -3-((4-methylpiperidin-1-yl) methyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3-((benzyl (methyl) amino) methyl) -4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
4- (2-methylphenyl) -3-((methyl (pyridin-2-ylmethyl) amino) methyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
4- (2-methylphenyl) -3-((methyl (pyridin-3-ylmethyl) amino) methyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
4- (2-methylphenyl) -3-((methyl (pyridin-4-ylmethyl) amino) methyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
4- (2- (4-fluorophenyl) cyclohex-1-en-1-yl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
4- (2-methyl-6-nitrophenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
4- (2-chloro-6-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1- (3- (1-naphthyloxy) propyl) -4- (2- (4-nitrophenyl) cyclohex-1-en-1-yl) -1H-indole-2-carboxylic acid;
4- (2- (3-methoxyphenyl) cyclohex-1-en-1-yl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
4- (5-fluoro-2-methyl-3-((methylsulfonyl) methyl) phenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -3-phenyl-1H-indole-2-carboxylic acid;
3-bromo-4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
4- (2-methylphenyl) -3-((4-methylphenyl) amino) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (4-hydroxyphenyl) -4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3-hydroxyphenyl) -4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -3-pyridin-4-yl-1H-indole-2-carboxylic acid;
4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -3-pyridin-3-yl-1H-indole-2-carboxylic acid;
3-cyano-4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3-bromo-5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
5- (benzyloxy) -1- (3- (1-naphthyloxy) propyl) -3- (2- (trifluoromethyl) phenyl) -1H-indole-2-carboxylic acid;
5-fluoro-3- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
5-fluoro-1- (3- (1-naphthyloxy) propyl) -3- (2- (trifluoromethyl) phenyl) -1H-indole-2-carboxylic acid;
5-fluoro-3- (2-isopropylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -3-((3- (trifluoromethoxy) phenyl) amino) -1H-indole-2-carboxylic acid;
5- (benzyloxy) -1- (3- (1-naphthyloxy) propyl) -3-((3- (trifluoromethoxy) phenyl) amino) -1H-indole-2-carboxylic acid;
5- (benzyloxy) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
5- (benzyloxy) -3- (2-isopropylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (2- (tert-butoxymethyl) phenyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
5-fluoro-1- (3- (1-naphthyloxy) propyl) -3- (2-((3- (trifluoromethyl) phenoxy) methyl) phenyl) -1H-indole-2-carboxylic acid;
5-chloro-3- (2-isopropylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
5-chloro-3- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
5-hydroxy-3- (2-isopropylphenyl) -1- (3- (5,6,7,8-tetrahydronaphthalen-1-yloxy) propyl) -1H-indole-2-carboxylic acid;
5-hydroxy-3- (2-isopropylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (2-isopropylphenyl) -5- (4-morpholin-4-ylbutoxy) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
5-fluoro-1- (3- (1-naphthyloxy) propyl) -3- (1,3,5-trimethyl-1H-pyrazol-4-yl) -1H-indole-2-carboxylic acid;
3- (2-isopropylphenyl) -1- (3- (1-naphthyloxy) propyl) -5-phenyl-1H-indole-2-carboxylic acid;
3- (2,6-dimethylphenyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (2-isopropylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1- (3- (1-naphthyloxy) propyl) -5-((1E) -pent-1-enyl) -1H-indole-2-carboxylic acid;
3- (2,6-dimethylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1- (3- (1-naphthyloxy) propyl) -3- (1,3,5-trimethyl-1H-pyrazol-4-yl) -1H-indole-2-carboxylic acid;
3- (2-chlorophenyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3-((1E) -5- (dimethylamino) pent-1-enyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3-((1E) -6-((2-carboxybenzoyl) amino) hex-1-enyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid acid;
3-((1E) -6-aminohex-1-enyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (6-aminohexyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (5- (dimethylamino) pentyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
6-chloro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (2-((1E) -5- (Dimethylamino) pent-1-enyl) phenyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid acid;
3- (2- (dimethylamino) phenyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
1-methyl-5- (4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indol-2-yl) -1H-pyrazol-3-ol;
4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -2- (1H-tetrazol-5-yl) -1H-indole;
And their therapeutically acceptable salts, prodrugs, esters, amides, prodrug salts, ester salts and amide salts.

  Yet another embodiment relates to a composition comprising an excipient and a therapeutically effective amount of a compound having Formula I.

  Yet another embodiment provides a mammal having a disease characterized by overexpression or unregulation of Mcl-1 protein, comprising administering to the mammal a therapeutically effective amount of a compound having Formula I. It relates to a method of treatment.

  Yet another embodiment comprises administering to a mammal a therapeutically effective amount of a compound having Formula I and one or more other therapeutic agents, and administering radiation therapy to the mammal. A method of treating a mammal having a disease characterized by overexpression or unregulation of Mcl-1 protein, with or without.

  The variable part of the compound herein is represented by an identification expression (capital letters with a superscript number and / or superscript alphabet), and can be expressed specifically.

  It is clear that the proper valence is maintained in all combinations in the present invention, monovalent moieties having multiple atoms are attached at the left end, and divalent moieties are drawn from left to right.

  It will also be apparent that the specific embodiment of the variable part may be the same or different from another specific embodiment having the same identification.

As used herein, the term “alkenyl” refers to one or more carbon-carbon doubles such as C ₂ -alkenyl, C ₃ -alkenyl, C ₄ -alkenyl, C ₅ -alkenyl, C ₆ -alkenyl and the like. It means a monovalent linear or branched hydrocarbon moiety having a bond.

As used herein, the term “alkenylene” refers to one or more carbon-carbon doubles such as C ₂ -alkenylene, C ₃ -alkenylene, C ₄ -alkenylene, C ₅ -alkenylene, C ₆ -alkenylene, and the like. It means a divalent linear or branched hydrocarbon moiety having a bond.

As used herein, the term “alkyl” refers to a monovalent saturated straight chain such as C ₁ -alkyl, C ₂ -alkyl, C ₃ -alkyl, C ₄ -alkyl, C ₅ -alkyl, C ₆ -alkyl, and the like. Means a chain or branched hydrocarbon moiety.

As used herein, the term “alkylene” refers to a divalent saturated straight chain such as C ₁ -alkylene, C ₂ -alkylene, C ₃ -alkylene, C ₄ -alkylene, C ₅ -alkylene, C ₆ -alkylene and the like. Means a chain or branched hydrocarbon moiety.

As used herein, the term “alkynyl” refers to one or more carbon-carbon triple bonds such as C ₂ -alkynyl, C ₃ -alkynyl, C ₄ -alkynyl, C ₅ -alkynyl, C ₆ -alkynyl and the like. Means a monovalent linear or branched hydrocarbon moiety having

As used herein, the term “alkynylene” refers to one or more carbon-carbon triple bonds such as C ₂ -alkynylene, C ₃ -alkynylene, C ₄ -alkynylene, C ₅ -alkynylene, C ₆ -alkynylene, and the like. Means a divalent linear or branched hydrocarbon moiety having

  As used herein, the term “C (O) OH biological equivalent” refers to substantially similar physical or chemical properties that provide similar biological properties as a compound having formula (I). Means a part having Examples of C (O) OH bioisosteres include isothiazol-3 (2H) -one 1,1-dioxide, isothiazolidine-3-one 1,1-dioxide, 1,2,4-oxadioxide Azol-5 (2H) -one, 1,2,5-thiadiazolidine-3-one 1,1-dioxide, 1,2,5-thiadiazol-3-ol, 1,2,4-oxadiazolidine- And monovalent groups derived from the elimination of one hydrogen atom from one molecule such as 3,5-dione, 2H-tetrazole and the like.

As used herein, the term “cycloalkane” refers to C ₄ -cycloalkane, C ₅ -cycloalkane, C ₆ -cycloalkane, C ₇ -cycloalkane, C ₈ -cycloalkane, C ₉ -cycloalkane. , C ₁₀ -cycloalkane, C ₁₁ -cycloalkane, C ₁₂ -cycloalkane and the like, a saturated cyclic or bicyclic hydrocarbon moiety.

The term “cycloalkyl” as used herein includes C ₃ -cycloalkyl, C ₄ -cycloalkyl, C ₅ -cycloalkyl, C ₆ -cycloalkyl, C ₇ -cycloalkyl, C ₈ -cycloalkyl. , C ₉ -cycloalkyl, C ₁₀ -cycloalkyl, C ₁₁ -cycloalkyl, C ₁₂ -cycloalkyl and the like, and monovalent saturated cyclic or bicyclic hydrocarbon moieties.

The term “cycloalkene” as used herein refers to C ₅ -cycloalkene, C ₆ -cycloalkene, C ₇ -cycloalkene, C ₈ -cycloalkene, C ₉ -cycloalkene, C ₁₀ -cycloalkene. , C ₁₁ -cycloalkene, C ₁₂ -cycloalkene and the like means a cyclic or bicyclic hydrocarbon moiety having one or more carbon-carbon double bonds.

The term “cycloalkenyl” as used herein refers to C ₄ -cycloalkenyl, C ₅ -cycloalkenyl, C ₆ -cycloalkenyl, C ₇ -cycloalkenyl, C ₈ -cycloalkenyl, C ₉ -cycloalkenyl. , C ₁₀ -cycloalkenyl, C ₁₁ -cycloalkenyl, C ₁₂ -cycloalkenyl, etc. means a monovalent cyclic hydrocarbon moiety having one or more carbon-carbon double bonds.

  As used herein, the term “heteroallene” refers to furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, 1,3,4- It means oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, 1,3,4-thiadiazole, thiophene, triazine and 1,2,3-triazole.

  As used herein, the term “heteroaryl” refers to furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, pyrazinyl , Pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl Means.

The term “heterocyclic alkane” as used herein refers to 1 or 2 or 3 CH ₂ moieties replaced with independently selected O, S, S (O), SO ₂ or NH and Means a cycloalkane having one or two CH moieties that are not replaced by N or are replaced by O, S, S (O), SO ₂ or NH that are not replaced or independently selected Also meant are cycloalkanes having 1 or 2 or 3 CH ₂ moieties and 1 or 2 CH moieties replaced by N.

As used herein, the term “heterocyclic alkene” refers to 1 or 2 or 3 CH ₂ moieties substituted with independently selected O, S, S (O), SO ₂ or NH and substituted. Means a cycloalkene having one or two CH moieties not substituted or replaced by N, and is replaced by O, S, S (O), SO ₂ or NH which is not replaced or independently selected Also meant are cycloalkenes having 1 or 2 or 3 CH ₂ moieties and 1 or 2 CH moieties replaced by N.

As used herein, the term “heterocyclic alkyl” refers to 1 or 2 or 3 CH ₂ moieties substituted with independently selected O, S, S (O), SO ₂ or NH and substituted. Means a cycloalkyl having 1 or 2 CH moieties not substituted or replaced by N, and is replaced by O, S, S (O), SO ₂ or NH that is not replaced or independently selected Also meant are cycloalkyls having 1 or 2 or 3 CH ₂ moieties and 1 or 2 CH moieties replaced with N.

The term “heterocyclic alkenyl” as used herein refers to 1 or 2 or 3 CH ₂ moieties substituted with independently selected O, S, S (O), SO ₂ or NH and Means cycloalkenyl with one or two CH moieties not substituted or replaced by N, replaced by O, S, S (O), SO ₂ or NH, not selected or independently selected Also meant are cycloalkenyl having 1 or 2 or 3 CH ₂ moieties and 1 or 2 CH moieties replaced by N.

  The term “cyclic moiety” as used herein refers to benzene, cycloalkane, cycloalkyl, cycloalkene, cycloalkenyl, heteroarene, heteroaryl, heterocyclic alkane, heterocyclic alkyl, heterocyclic alkene, heterocyclic alkenyl, Means phenyl and spiroalkyl.

  The compounds of the present invention may contain asymmetrically substituted carbon atoms in the R or S configuration, and the terms “R” and “S” are described in the literature (Pure Appl. Chem. (1976) 45, 13-10). As defined. Compounds having asymmetrically substituted carbon atoms containing equal amounts of R and S configurations are racemic at those atoms. Atoms that are in excess of one configuration relative to the other are assigned to configurations that are in excess, preferably about 85% to 90% excess, more preferably about 95% to 99% excess, more preferably about 99%. Excess over%. The invention therefore encompasses its racemic mixtures, relative and absolute diastereomers and compounds.

  The compounds of the present invention may also contain a carbon-carbon double bond or a carbon-nitrogen double bond in the Z or E configuration, wherein the term “Z” is on the same side of the carbon-carbon or carbon-nitrogen double bond. It represents that there are two relatively large substituents, and the term “E” indicates that there are two relatively large substituents on the opposite side of the carbon-carbon or carbon-nitrogen double bond. The compounds of the present invention may also exist as a mixture of “Z” and “E” isomers.

NH, C (O) H, C (O) OH, the compounds of the invention containing C (O) _NH 2, OH or SH moieties, prodrug formation portions may be bonded. Prodrug formation portion is eliminated by metabolic processes to release NH free in vivo, C (O) H, C (O) OH, a compound having a C (O) _NH 2, OH or SH. Prodrugs are useful in modulating the pharmacokinetic properties of compounds such as solubility and / or hydrophobicity, gastrointestinal absorption, bioavailability, tissue penetration and clearance rate.

  Metabolites of compounds having Formula I produced by in vitro or in vivo metabolic processes may also be useful in the treatment of diseases caused or exacerbated by overexpressed or unregulated Mcl-1 protein.

  Thus, certain precursor compounds of compounds having formula I that can be metabolized in vitro or in vivo to form compounds of formula I are also caused or exacerbated by overexpressed or unregulated Mcl-1 protein. May be useful in the treatment of the disease.

  Compounds having formula I can exist as acid addition salts, base addition salts or zwitterions. A salt of a compound having formula I is prepared upon its isolation or subsequent purification thereof. Acid addition salts are those derived from reaction of a compound having formula I with an acid. Thus, acetates, adipates, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate of the compounds having formula I , Camphorate, camphorsulfonate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, iodine Hydrohalide, lactobionate, lactate, maleate, mesitylene sulfonate, methane sulfonate, naphthylene sulfonate, nicotinate, oxalate, pamoate, pectate, persulfate Salt, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetate, trifluoroacetate, para-toluenesulfonate and Salts such undecanoate are intended to be encompassed by the present invention. Base addition salts of compounds are those derived from the reaction of a compound having Formula I with a bicarbonate, carbonate, hydroxide or phosphate of a cation such as lithium, sodium, potassium, calcium and magnesium. .

  Compounds having formula I can be administered, for example, by buccal administration, ocular administration, oral administration, osmotic administration, parenteral administration (muscular administration, intraperitoneal administration, intrasternal administration, intravenous administration, subcutaneous administration), rectal administration, topical administration, trans It can be administered through the skin and vaginal.

  The therapeutically effective amount of the compound having Formula I is determined by the subject being treated, the disease being treated and its severity, the composition comprising it, the time of administration, the route of administration, the duration of administration, the efficacy, the clearance rate and the other agent used in combination. It depends on the presence or absence. The amount of the compound having Formula I used in preparing a composition to be administered to a patient daily in single or divided doses is from about 0.001 to about 200 mg / kg. Single dose compositions comprise these amounts or a combination of subparts thereof.

  The compound having Formula I can be administered with or without an excipient. Excipients include, for example, capsules and absorption enhancers, antioxidants, binders, buffers, coating agents, colorants, diluents, disintegrants, emulsifiers, extenders, fillers, flavoring agents, humectants. And additives such as lubricants, fragrances, preservatives, propellants, mold release agents, sterilizers, sweeteners, solubilizers, wettable agents and mixtures thereof.

Compounds having Formula I are carbon (ie ¹³ C), hydrogen (ie ³ H), nitrogen (ie ¹⁵ N), phosphorus (ie ³² P), sulfur (ie ³⁵ S) or iodine (ie ¹²⁵ I), etc. It can also be radiolabeled with a radioisotope. A radioactive isotope can be incorporated into a compound by reacting the compound having Formula I with a radioinducing agent or by incorporating a radiolabeled intermediate in its synthesis. The radiolabeled compounds of formula I are useful for both prognostic and diagnostic applications and for in vivo and in vitro imaging.

Compounds having Formula I include, but are not limited to, arteriovenous implants, biliary stents, bypass implants, catheters, central nervous system shunts, coronary stents, drug delivery balloons, peripheral stents and ureteral stents. Each of which is used in a region such as, but not limited to, the vasculature to introduce a compound having Formula I into a selected tissue or organ in the body. be able to.
One measure of the effectiveness of a compound having Formula I is the reduction or elimination of device-related thrombi and associated complications.

  Compounds having formula I can be used as radiosensitizers that increase the efficacy of radiation therapy. Examples of radiation therapy include, but are not limited to, external radiation therapy, teletherapy, brachytherapy, and sealed and unsealed radiation therapy.

  Excipients for the manufacture of compositions containing compounds having formula I to be administered orally include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor Oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cros-povidone, diglycerides, ethanol, ethylcellulose, ethyl laurate, ethyl oleate, fatty acid ester, gelatin, germ oil, glucose, glycerin, peanut oil , Hydroxypropylmethylcellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato Open water, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactant, talc, tragacanth , Tetrahydrofurfuryl alcohol, triglycerides, water and mixtures thereof. Excipients in the manufacture of a composition comprising a compound having the formula I administered orally or orally include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, sorbitan fatty acid ester, germ oil , Peanut oil, glycerin, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water and mixtures thereof. Excipients for preparing a composition comprising a compound having Formula I that is administered osmotically include, for example, chlorofluorocarbons, ethanol, water, and mixtures thereof. Excipients in the manufacture of compositions comprising compounds having formula I administered parenterally include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, glucose, germ oil, peanut oil, liposomes Oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.A. S. P. Or isotonic sodium chloride solution, water and mixtures thereof. Excipients in the manufacture of a composition comprising a compound having Formula I for rectal or vaginal administration include, for example, cocoa butter, polyethylene glycol, waxes and mixtures thereof.

Assay On a 433A automated synthesizer (Applied Biosystems, Foster City, Calif.) Using a standard Fastmoc ™ deprotection / coupling cycle using 0.25 mmol MBHA Rink amide resin (SynPep, Dublin, Calif.) Fam) -NoxaCF (6-FAM) -GELEVEFATQLRRFGDKLNF-amide) (SEQ ID NO: 1) was prepared. Side chain protection (Arg: 2,2,5,7,8-pentamethylchroman-6-sulfonyl; Asp and Glu: tert-butyl ester; Asn, Cys, Gln and His: trityl; Lys and Trp: tert-butyl A cartridge containing N ^α -Fmoc-amino acids (1 mmol) subjected to oxycarbonyl; Ser, Thr and Tyr: tert-butyl ether) was added in N-methylpyrrolidone (NMP) with O-benzotriazol-1-yl- Activated with N, N, N ′, N′-tetramethyluronium hexafluorophosphate (1 mmol), 1-hydroxybenzotriazole (1 mmol) and diisopropylethylamine (2 mmol). After removal of the N-terminal Fmoc group with 20% piperidine in NMP, the activated amino acid was coupled for 30 minutes. Suspension of resin-bound N-terminal deprotected side-chain protected peptide resin (0.04 mmol) and 6-carboxyfluorescein-NHS ester (57 mg) in dehydrated dimethylformamide (2 mL) containing 0.02 mL of diisopropylethylamine (DIEA) And labeling was performed by shaking overnight at room temperature. The resin was drained, washed 3 times with 1: 1 dichloromethane / methanol and dried. Labeled resin was added at room temperature with TFA: water: thioanisole: phenol: 3,6-dioxa-1,8-octanedithiol: triisopropylsilane, 80: 5: 5: 5: 2.5: 2.5 Cleavage and deprotection were achieved by mixing for 3 hours. After the solvent was distilled off under reduced pressure, the crude peptide was recovered by precipitation with ether. A 25 mm × 200 mm radial compression column packed with Delta-Pak C ₁₈ packing (Waters, Inc., Taunton, Mass.) At a flow rate of 20 mL / min, using Unipoint analysis software (Gilson, Inc., The product was purified by preparative HPLC using Middleton, WI). Peptides were eluted using a linear gradient of 0.1% TFA / water and acetonitrile. Fractions containing product were combined and lyophilized. Diode array eluting with a linear gradient of 0.1% trifluoroacetic acid / water and acetonitrile on a 4.6 × 250 mm YMC ODS-AQ, 5 μm, 120Å column (Waters Inc.) and fluorescence detection (Agilent Technologies, Palo Alto, The purity of the final product was confirmed by reverse phase analytical HPLC on a Hewlett-Packard 1050 series system using CA) to give the product (45.6 mg) as a yellow powder after lyophilization. . The product was identified by matrix-assisted laser desorption / ionization mass spectrometry (MALDI-MS) on Voyager DE-PRO (Applied Biosystems) and was m / z 1470.00 and 1444.81 (M + H) ⁺ .

IC ₅₀ measurements of compounds with representative Formula I against recombinant Mcl-1 protein were made using a fluorescence polarization assay. Starting from 10 μM, compounds were serially diluted with DMSO and transferred to 96-well plates (5 μL). Next, 120 μL of a mixture containing 10 nM fluorescent NoxaBH ₃ peptide and 80 nM Mcl-1 protein was added to each well. For each assay, a free peptide control (fluorescent peptide only) and a bound peptide control (fluorescent peptide in the presence of Mcl-1) were included in each assay plate. The plate was mixed on a shaker for 1 minute and incubated at room temperature for an additional 15 minutes. Polarization (in mP) was measured at room temperature with an excitation wavelength of 485 nm and an emission wavelength of 530 nm using an Analyst (LJL, Molecular Dynamic, Sunnyvale, CA). Percent inhibition was calculated by% inhibition = 100 × (1− (mP−mP _f ) / (mP _b −mP _f )) (mP _f is a free peptide control and mP _b is a binding peptide control). Based on the percent inhibition, the inhibition data was adapted using Prism 3.0 software (Graphpad Software Inc., San Diego, Calif.) To obtain an IC ₅₀ (inhibitor concentration at which 50% of the bound peptide was replaced). It was. The results are shown in Table 1.

  These data demonstrate the utility of the compounds having representative Formula I as inhibitors of Mcl-1 protein activity.

  These data demonstrate the utility of the compounds having representative Formula I as inhibitors of Mcl-1 protein activity.

Thus, compounds of formula I are, during the anti-apoptotic McI-1 are useful in the treatment of diseases that are expressed are expected, for example, _{BCl-X L} protein, Bcl-2 protein and Bcl-w protein, etc. It is expected to be useful in the treatment of diseases in which anti-apoptotic family protein members having close structural homology to Mcl-1 are expressed.

  Overexpression of Mcl-1 is acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic (Spherical and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer (including estrogen receptor positive breast cancer), bronchial cancer, cervical cancer, chondrosarcoma, chordoma , Choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B cell Lymphoma, abnormal growth changes (dysplasia and metaplasia), embryonal cancer, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing tumor, fibrosarcoma, follicular lymphoma, gastric cancer, embryo Cancer of the testicle, gestational choriocarcinoma, glioblastoma, head and neck cancer, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, fat Sarcoma, lung cancer (including small cell lung cancer and non-small cell lung cancer), lymphatic endothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma and non Lymphomas such as Hodgkin lymphoma), bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterine malignancies and hyperproliferative disorders, lymphoid malignancies of T or B cell origin, leukemia, lymphoma, medullary Cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, non-small cell lung cancer, oligodendroglioma, oral cancer , Osteogenic sarcoma, egg Cancer, pancreatic cancer, papillary adenocarcinoma, papillary cancer, peripheral T-cell lymphoma, pineal gland, polycythemia vera, prostate cancer (hormone-insensitive (refractory) prostate cancer, etc.), kidney cancer, renal cell cancer, retina Blastoma, rhabdomyosarcoma, sarcoma, sebaceous carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumor (cancer and sarcoma), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovial tumor For chemotherapy in various forms of hematological and solid tumors such as sweat gland cancer, testicular cancer (including germ cell testicular cancer), thyroid cancer, Waldenstrom macroglobulinemia, testicular tumor, uterine cancer, Wilms tumor It is related to tolerance, clinical outcome, disease progression, overall prognosis, or a combination thereof.

  The compound having Formula I is fetal rhabdomyosarcoma, childhood acute lymphoblastic leukemia, childhood acute myeloid leukemia, childhood alveolar rhabdomyosarcoma, childhood anaplastic ependymoma, childhood anaplastic large cell lymphoma, Ewing such as childhood anaplastic medulloblastoma, childhood atypical teratoma / rhabdomyosarcoma of the central nervous system, childhood biphenotypic acute leukemia, childhood Burkitt lymphoma, and undifferentiated neuroectodermal tumor Childhood cancer of the tumor, childhood diffuse undifferentiated Wilms tumor, childhood histology good Wilms tumor, childhood glioblastoma, childhood medulloblastoma, childhood neuroblastoma, childhood neuroblastoma-derived myelocytoma, childhood Inhibits pediatric cancer or tumor-derived cell growth such as pre-B cell carcinoma (such as leukemia), pediatric osteosarcoma (psteosarcoma), pediatric renal rod tumor, pediatric T-cell cancer such as rhabdomyosarcoma and lymphoma, and skin cancer To do They are virtual.

  The involvement of Mcl-1 in acute lymphoblastic leukemia has been reported in the literature (Blood 1998, 91, 991-1000).

  The involvement of Mcl-1 in acute myeloid leukemia has been reported in the literature (Blood 1998, 91, 991-1000).

  The involvement of Mcl-1 in cervical cancer has been reported in the literature (Cancer Letters (Shannon, Ireland) 2002, 180, 63-68).

  The involvement of Mcl-1 in chronic lymphocytic leukemia has been reported in the literature (Journal of the National Cancer Institute 2004, 96, 673-682 and Immunology 2005, 114, 441-449).

  The involvement of Mcl-1 in colorectal cancer has been reported in the literature (Annals of oncology: Official Journal of the European Society for Medical Oncology / ESMO 2001, 12, 779-785).

  The involvement of Mcl-1 in gastric cancer has been reported in the literature (Gastric Cancer 2004, 7, 78-84).

  The involvement of Mcl-1 in gestational chorionic disease has been reported in the literature (Cancer 2005, 103, 268-276.).

  The involvement of Mcl-1 in glioblastoma has been reported in the literature (Journal of Neurology, Neurosurgery and Psychiatry 1999, 67, 763-768).

  The involvement of Mcl-1 in head and neck cancer has been reported in the literature (Archives of Otolaryngology-Head and Neck Surgery 1999, 125, 417-422).

  The involvement of Mcl-1 in lung cancer has been reported in the literature (Pathology Oncology Research: POR 1999, 5, 179-186).

  The involvement of Mcl-1 in mesothelioma has been reported in the literature (Clinical Cancer Research 1999, 5, 3508-3515).

  The involvement of Mcl-1 in multiple myeloma has been reported in the literature (European Journal of Immunology 2004, 34, 3156-3164).

  The involvement of Mcl-1 in non-Hodgkin lymphoma has been reported in the literature (British Journal of Haematology 2002, 116, 158-161).

  The involvement of Mcl-1 in oligodendroglioma has been reported in the literature (Cancer (New York) 1999, 86, 1832-1839).

  The involvement of Mcl-1 in ovarian cancer has been reported in the literature (Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 2000, 18, 3775-3781).

  The involvement of Mcl-1 in pancreatic cancer has been reported in the literature (Oncology 2002, 62, 354-362).

  The involvement of Mcl-1 in peripheral T-cell lymphoma has been reported in the literature (Journal of Pathology 2003, 200, 240-248).

  Compounds having Formula I include alkylating agents, angiogenesis inhibitors, antibiotics, antimetabolites, antimitotic agents, antiproliferative agents, Aurora kinase inhibitors, Bcl-2 family proteins (eg, Bcl-xL, Bcl-2, Bcl-w, Bfl-1) inhibitor, Bcr-Abl kinase inhibitor, biological response regulator, cyclin-dependent kinase inhibitor, cell cycle inhibitor, cyclooxygenase-2 inhibitor, leukemia virus oncogene homology Body (ErbB2) receptor inhibitor, growth factor inhibitor, heat shock protein (HSP) -90 inhibitor, histone deacetylase (HDAC) inhibitor, hormonal therapy, immunity agent, insertion antibiotic, kinase inhibitor, rapamycin (Rapomycin) inhibitors of mammalian targets, mitogen-activated extracellular signal-regulated kinase inhibitors, non-steroidal anti-steroids Drugs (NSAIDs), platinum chemotherapeutic drugs, polo-like kinase inhibitors, proteasome inhibitors, purine analogues, pyrimidine analogues, receptor tyrosine kinase inhibitors, retinoid / deltoids plant alkaloids, topoisomerase inhibitors It is expected to be useful when used together with the above.

  Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, carbocon, carmustine (BCNU), chlorambucil, chloretadine (trade name) (VNP40101M), cyclophos Famide, decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitoblonitol, mitactol, nimustine, nitrogen mustard N-oxide, ranimustine , Temozolomide, thiotepa, treosulphane, trophosphamide and the like.

  Angiogenesis inhibitors include endothelium-specific receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix Metalloproteinase-2 (MMP-2) inhibitor, matrix metalloproteinase-9 (MMP-9) inhibitor, platelet-derived growth factor receptor (PDGFR) inhibitor, thrombospondin analog, vascular endothelial growth factor receptor Examples include tyrosine kinase (VEGFR) inhibitors.

  Aurora kinase inhibitors include AZD-1152, MLN-8054, VX-680 and the like.

  Bcl protein family member inhibitors include AT-101 ((-) gossypol), genasense (G3139 or oblimersen (Bcl-2 targeted antisense oligonucleotide)), IPI-194, IPI-565, N- (4- (4-((4′-Chloro (1,1′-biphenyl) -2-yl) methyl) piperazin-1-yl) benzoyl) -4-(((1R) -3- (dimethylamino) -1- ((Phenylsulfanyl) methyl) propyl) amino) -3-nitrobenzenesulfonamide) (ABT-737), N- (4- (4-((2- (4-chlorophenyl) -5,5-dimethyl-1-) Cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoyl) -4-(((1R) -3- (morpholin-4-yl)- - and the like ((trifluoromethyl) sulfonyl) benzenesulfonamide (ABT-263), GX-070 (Oba Useful Lux) - ((phenylsulfanyl) methyl) propyl) amino) -3.

  Bcr-Abl kinase inhibitors include dasatinib (registered trademark) (BMS-354825), Gleevec (registered trademark) (imatinib) and the like.

  CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopiridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, celicrib (CYC-202, R-roscovitine) and ZK-304709.

  COX-2 inhibitors include ABT-963, Alkoxya® (Etricoxib), Bextra® (Valdecoxib), BMS347070, Celebrex ™ (celecoxib), COX-189 (Lumiracoxib), CT-3, Delamax (registered trademark) (Delacoxib), JTE-522, 4-methyl-2- (3,4-dimethylphenyl) -1- (4-sulfamoylphenyl-1H-pyrrole), MK- 663 (ethricoxib), NS-398, paracoxib, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T-614, Biox (registered trademark) (rofecoxib), and the like.

  EGFR inhibitors include ABX-EGF, anti-EGFr immunoliposomes, EGF-vaccine, EMD-7200, Erbitux® (cetuximab), HR3, IgA antibody, Iressa® (gefitinib), Tarceva ( (Registered trademark) (erlotinib or OSI-774), TP-38, EGFR fusion protein, Tycurb (registered trademark) (lapatinib) and the like.

  ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib), Herceptin® (Trastuzumab), Tykerb® (Lapatinib), Omnitag® (2C4, Pertuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), Anti-HER / 2neu bispecific antibody, B7. her2IgG3, AS HER2 trifunctional bispecific antibody, mAB AR-209, mAB 2B-1.

  Histone deacetylase inhibitors include depsipeptides, LAQ-824, MS-275, trapoxin, suberoylilide hydroxamic acid (SAHA), TSA, valproic acid and the like.

  HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, mycograb (MYCOGRAB; Registered trademark), NCS-683664, PU24FC1, PU-3, Radicicol, SNX-2112, STA-9090, VER49009, and the like.

  MEK inhibitors include ARRY-142886, ARRY-438162PD-325901, PD-98059 and the like.

  mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus and the like.

  Non-steroidal anti-inflammatory drugs include AMIGESIC (registered trademark) (salsalate), Drobid (registered trademark) (diflunisal), Motrin (registered trademark) (ibuprofen), Ordis (registered trademark) (ketoprofen), Lerafen (registered) (Trademark) (Nabumetone), Felden (Piroxicam) ibuprofin cream, Alive (R) and Naprosin (Naproxen), Voltaren (R) (Diclofenac), Indosine (R) (Indomethacin), Crinolyl (R) (Trademark) (Sulindac), Trectin (registered trademark) (tolmetin), rosin (LODINE; registered trademark) (etodolac), tradol (registered trademark) (ketorolac), Daipro (registered trademark) (oxaprozin) and the like.

  PDGFR inhibitors include C-451, CP-673, CP-868596, and the like.

  Platinum chemotherapeutic agents include cisplatin, Eloxatin (registered trademark) (oxaliplatin), eptaplatin, lovaplatin, nedaplatin, paraplatin (registered trademark) (carboplatin), satraplatin and the like.

  Polo-like kinase inhibitors include BI-2536.

  Examples of thrombospondin analogs include ABT-510, ABT-567, ABT-898, and TSP-1.

  Examples of VEGFR inhibitors include Avastin (registered trademark) (bevacizumab), ABT-869, AEE-788, angiozyme (trade name), actininib (AG-13736), AZD-2171, CP-547,632, IM-862. , Mcgen (Pegaptanib), Nexavar (registered trademark) (Sorafenib, BAY 43-9006), Pazopanib (GW-786034), (PTK-787, ZK-222584), Sutent (registered trademark) (Sunitinib, SU-11248), VEGF Examples include scavengers, batalanib, Zactima (trade name) (vandetanib, ZD-6474).

  Antimetabolites include Alimta (premetrexed disodium, LY231514, MTA), 5-azacytidine, Xeloda (registered trademark) (capecitabine), Carmofur, Leustat (registered trademark) (LEUSTAT) (Cladribine) ), Clofarabine, cytarabine, cytarabine ocphosphate, cytosine arabinoside, decitabine, deferoxamine, doxyfluridine, efflornitine, EICAR, enocitabine, ethynylcytidine, fludarabine, hydroxyurea, 5-fluorouracil (5-FU) alone or in combination with leucovorin (Registered trademark) (gemcitabine), hydroxyurea, alkeran (registered trademark) (melphalan), mercaptopurine, 6-mercaptopurine riboside, metoto Xetate, mycophenolic acid, nelarabine, noratrexed, ocfosate, peritrexol, peltostatin, raltitrexed, ribavirin, triapine, trimetrexate, S-1, thiazofurin, tegafur, TS-1, vidarabine, There is UFT.

  Antibiotics include the insertion antibiotics aclarubicin, actinomycin D, amrubicin, anamycin, adriamycin, brenoxane® (bleomycin), daunorubicin, caelix (CAELYX) or myocet (MYOCET) (doxorubicin), elsamitrucin, epirubucin (Epirbucin), glarbuicin (glarbuicin), zabedos (idarubicin), mitomycin C, nemorubicin, neocartinostatin, pepromycin, pirarubicin, rebeccamycin, styramer, streptozocin, VALSTAR (valrubicin), dinostatin and the like.

  Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarine, beotecan, BN-80915, camptosar® (irinotecan hydrochloride), camptothecin, cardioxan® ( CARDIOXANE) (dexrazoxane), difuromotecan, edotecarin, Elens (registered trademark) or farmorubicin (registered trademark) (epirubicin), etoposide, exatecan, 10-hydroxycamptothecin, dimatecan, luruthecan, mitoxantrone, olathecin, pirarubucine (Pirarbucin), pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, topotecan and the like.

  The antibodies include: Avastin (registered trademark) (bevacizumab), CD40 specific antibody, chTNT-1 / B, denosumab, Erbitux (registered trademark) (cetuximab), HUMAX-CD4 (registered trademark) (zanolimumab), IGF1R specific antibody, lintuzumab , Panorex (registered trademark) (Edrecolomab), RenCAREX (registered trademark) (WXG250), Rituxan (registered trademark) (rituximab), ticilimumab, trastuzimab and the like.

  Hormone therapy includes Arimidex (registered trademark) (anastrozole), Aromasin (registered trademark) (exemestane), Arzoxifene, Casodex (registered trademark) (bicalutamide), Cetrotide (registered trademark) (setrorelix), Degarelix, Deslorelin , Desopan® (Trilostane), Dexamethasone, Drogenil® (Flutamide), Evista® (Raloxifene), Fadrozole, Fairston® (Tremifene), Faslodex® ( Fulvestrant), femara (registered trademark) (letrozole), formestane, glucocorticoids, hectrol (registered trademark) or linagel (registered trademark) (doxelcalciferol), lasofoxifene, leucoacetate Lolide, Megeth (R) (Megesterol), Mifeplex (R) (Mifepristone), Nilandron (R) (Nilutamide), Norbadex (R) (Tamoxifen Citrate), Plenaxis (R) (Abarelix), Predisone, Propecia® (Finasteride), Lilostane, Sprefact® (Buserellin), Trelster® (Luteinizing Hormone Releasing Hormone (LHRH)), Vantas (Vantas), Betril (registered trademark) (trilostane or modrastane), Zoladex (registered trademark) (Fosrelin, Goserelin) and the like.

  Delotoids / retinoids include seocalcitol (EB1089, CB1093), lexacalcitrol (KH1060), fenretinide, panretin (registered trademark) (aliretinoin), and ATRAGEN (registered trademark). (Liposomeized tretinoin), tagretin (registered trademark) (bexarotene), LGD-1550 and the like.

  Plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like.

  Proteasome inhibitors include Velcade (registered trademark) (bortezomib), MG132, NPI-0052, PR-171 and the like.

  Examples of immunizing agents include interferons and other immunostimulatory agents. Examples of interferons include interferon α, interferon α-2a, interferon α-2b, interferon β, interferon γ-1a, ACTIMMUNE (interferon γ-1b), interferon γ-n1, and combinations thereof. Other drugs include ALFAFERONE, BAM-002, BEROMUN (registered trademark) (Tasonermin), Bexar (registered trademark) (tositumomab), Campus (registered trademark) (alemtuzumab), CTLA4 (cytotoxicity) Lymphocyte antigen 4), decarbazine, denileukin, epratuzumab, granosite (registered trademark) (Lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010, melanoma vaccine, mitumomab, morgramostim, mylotag (trade name) (Gemtuzumab ozogamicin), Newpogen (registered trademark) (filgrastim), OncoVAC-CL, Ovalex (registered trademark) (oregobomab), pemtumomab (Y-muHMFG1), Provenge (Registered trademark), sargaramostim, schizophyllan, teseleukin, TheraCys (registered trademark), ubenimex, virulidine (registered trademark), Z-100, WF-IO, proleukin (registered trademark) (aldesleukin), zadaxin (registered trademark) ) (Simalfacin), Xenapacs (registered trademark) (daclizumab), Zevalin (registered trademark) (90Y-ibritumomab tiuxetane), and the like.

  The biological response modifier is an agent that changes the biological defense mechanism such as the defense mechanism of the living body or the survival, proliferation or differentiation of tissue cells to give them antitumor activity. Krestin, lentinan, schizophyllan, picibanil PF− 3512676 (CpG-8954), Ubenimex and the like.

  Pyrimidine analogs include cytarabine (ara C or arabinoside C), cytosine arabinoside, doxyfluridine, fludara (registered trademark) (fludarabine), 5-FU (5-fluorouracil), floxuridine, gemzar (registered trademark) (gemcitabine) ), Tomdex (registered trademark) (ratitrexed), and troxatil (trade name) (triacetyluridine troxacitabine).

Purine analogs include Lambis (registered trademark) (thioguanine) and Prinetol (registered trademark) (mercaptopurine).
And mitotic inhibitors include batabulin, epothilone D (KOS-862), N- (2-((4-hydroxyphenyl) amino) pyridin-3-yl) -4-methoxybenzenesulfonamide, ixabepilone (BMS247550) ), Paclitaxel, taxotere (registered trademark) (docetaxel), PNU100940 (109881), papillon, XRP-9881, vinflunine, ZK-EPO and the like.

  The compounds of the present invention are also used as radiosensitizers that increase the efficacy of radiotherapy. Examples of radiation therapy include, but are not limited to, external radiation therapy, teletherapy, brachytherapy, and sealed and unsealed radiation therapy.

  In addition, compounds having Formula I are Abraxane ™ (ABI-007), ABT-100 (farnesyl transferase inhibitor), Advexin®, ALTOCOR®, or Mebacol®. (Lovastatin), ampligen (registered trademark) (polyI: polyC12U, synthetic RNA), aptosine (trade name) (excislind), aredia (registered trademark) (pamidronic acid), algravin, L-asparaginase, atamestan (1-methyl- 3,17-dione-androst-1,4-diene), Avage® (Tazarotene), AVE-8062, BEC2 (mitumomab), cachectin or cachexin (tumor necrosis factor), can Baxin (vaccine), Ce Vac (trade name) (cancer vaccine), Celoique (registered trademark) (Cermoleukin), CEPLENE (registered trademark) (histamine dihydrochloride), Cellvarix (trade name) (human papillomavirus vaccine), CHOP ( (Registered trademark) (C: cytoxan (registered trademark) (cyclophosphamide); H: adriamycin (registered trademark) (hydroxydoxorubicin); O: vincristine (oncobin (registered trademark)); P: prednisone), CyPat (trade name) ), Combrestatin A4P, DAB (389) EGF or TransMID-107R (trade name) (diphtheria toxin), dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), eniluracil , EVIZON (trade name) (Lactic acid squa Min), DIMERICINE (registered trademark) (T4N5 liposome lotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurine, EPO906, Gardasil (registered trademark) (tetravalent human papillomavirus (6, 11) , 16, 18) recombinant vaccine), gastrimune, genasense, GMK (ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine), halofuginone, histrelin, hydroxycarbamide, ibandronic acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (Sintredekin Bestos), IL-13 Pseudomonas exotoxin, interferon-α, interferon-γ, Genoban (trade name) or mepact (Trade name) (mifamultide), lonafanib, 5,10-methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine), NEOVASTAT (registered trademark) (AE-941), neutrexin (registered trademark) (Trimetrexate glucuronate), NIPENT (registered trademark) (pentostatin), Onconase (registered trademark) (ribonuclease enzyme), Oncophage (registered trademark) (melanoma vaccine treatment), OncoVAX (OncoVAX) ( IL-2 vaccine), oratecin (ORATHECIN; trade name) (rubitecan), OSIDEM (registered trademark) (antibody cell drug), OvaRex (registered trademark) MAb (mouse monoclonal antibody), pajitaxel ( paditaxel), Pandimex (trade name) ( Aglycone saponins from ginseng containing 0 (S) protopanaxadiol (aPPD) and 20 (S) protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (cancer vaccine under investigation) , Pegaspargase, PEG interferon A, phenoxodiol, procarbazine, levimastat, REMOVAB (registered trademark) (katsumaxomab), Revlimid (registered trademark) (lenalidomide), RSR13 (efaproxiral), somatrine ( (Registered trademark) LA (lanreotide), soriatan (registered trademark) (acitretin), staurosporine (streptomyces star spore), talabostato (PT100), tagretin (registered trademark) (bexarotene), taxa plexin (registered trademark) (DHA-paclitaxel), TELCYTA (trade name) (TLK286), temilifene (temilifene), temodarl (registered trademark) (temozolomide), tesmilifene, thalidomide, THERATOPE (registered trademark) (STn-KLH) ), Mimitac (2-amino-3,4-dihydro-6-methyl-4-oxo-5- (4-pyridylthio) quinazoline dihydrochloride), TN Ferade ™ (adenovector: tumor necrosis factor-α) DNA carrier containing the gene of), Thraclear (registered trademark) or Zaveska (registered trademark) (Bosentan), tretinoin (Retin-A), tetrandrine, Trisenox (registered trademark) (arsenic trioxide), Virulidine (registered trademark), Ukrain (alkaloids from celandine plants) Derivatives), vitaxin (anti-αvβ3 antibody), xytrin (registered trademark) (motexafingadolinium), XINLAY (trade name) (Atrasentan), XYOTAX (trade name) (paclitaxel polygourax), It can be combined with other chemotherapeutic agents such as Yondelis ™ (Trabectedin), ZD-6126, Zynecard® (dexrazoxane), Zometha (zoledronic acid), Zorubicin.

  The compound having Formula I is fetal rhabdomyosarcoma, childhood acute lymphoblastic leukemia, childhood acute myeloid leukemia, childhood alveolar rhabdomyosarcoma, childhood anaplastic ependymoma, childhood anaplastic large cell lymphoma, Children with Ewing tumors such as pediatric anaplastic medulloblastoma, pediatric atypical teratomas / rhabdomyosarcoma of the central nervous system, pediatric mixed acute leukemia, pediatric Burkitt lymphoma, anaplastic neuroectodermal tumor Cancer, Pediatric diffuse undifferentiated Wilms tumor, Pediatric histology Wilms tumor, Pediatric glioblastoma, Pediatric medulloblastoma, Pediatric neuroblastoma, Pediatric neuroblastoma-derived myelocytoma, Pediatric pre-B cell It is also expected to inhibit pediatric cancer or tumor-derived cell growth such as cancer (leukemia), childhood osteosarcoma, childhood renal thyroid tumor, childhood rhabdomyosarcoma and lymphoma, childhood T cell cancer and skin cancer ( Co-owned usa Application No. 10/9833838), Cancer Res., 2000, 60, 6101-10), acquired immune deficiency syndrome, autoimmune lymphoproliferative syndrome, hemolytic anemia, inflammatory disease Thrombocytopenia (Current Allergy and Asthma Reports 2003, 3: 378-384; Br. J. Haematol. 2000 Sep; 110 (3): 584-90; Blood 2000 Feb 15; 95 (4): 1283 -92; and New England Journal of Medicine 2004 Sep; 351 (14): 1409-1418).

Compounds having formula I can be prepared by synthetic chemical processes, examples of which are given below. The order of the steps in the processes can be varied, and the reagents, solvents and reaction conditions can be changed from those specifically mentioned, C (O) OH, C (O) and C (O It should be understood that weak moieties such as H), NH, C (O) NH ₂ , OH and SH moieties can be protected and deprotected as needed.

  Protecting groups for the C (O) OH moiety include acetoxymethyl, allyl, benzoylmethyl, benzyl, benzyloxymethyl, tert-butyl, tert-butyldiphenylsilyl, diphenylmethyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, diphenyl Methylsilyl, ethyl, para-methoxybenzyl, methoxymethyl, methoxyethoxymethyl, methyl, methylthiomethyl, naphthyl, para-nitrobenzyl, phenyl, n-propyl, 2,2,2-trichloroethyl, triethylsilyl, 2- ( Examples include, but are not limited to, trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, and triphenylmethyl.

  Protecting groups for C (O) and C (O) H moieties include 1,3-dioxy ketals, diethyl ketals, dimethyl ketals, 1,3-dithianyl ketals, O-methyl oximes, O-phenyl oximes, and the like. However, it is not limited to these.

  Protecting groups for the NH moiety include acetyl, alanyl, benzoyl, benzyl (phenylmethyl), benzylidene, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), 3,4-dimethoxybenzyloxycarbonyl, diphenylmethyl, diphenyl There are phosphoryl, formyl, methanesulfonyl, para-methoxybenzyloxycarbonyl, phenylacetyl, phthaloyl, succinyl, trichloroethoxycarbonyl, triethylsilyl, trifluoroacetyl, trimethylsilyl, triphenylmethyl, triphenylsilyl, para-toluenesulfonyl, etc. However, it is not limited to these.

  Protecting groups for the OH and SH moieties include acetyl, allyl, allyloxycarbonyl, benzyloxycarbonyl (Cbz), benzoyl, benzyl, tert-butyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, 3,4-dimethoxy Benzyl, 3,4-dimethoxybenzyloxycarbonyl, 1,1-dimethyl-2-propenyl, diphenylmethyl, formyl, methanesulfonyl, methoxyacetyl, 4-methoxybenzyloxycarbonyl, para-methoxybenzyl, methoxycarbonyl, methyl, para -Toluenesulfonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloroethyl, triethylsilyl, trifluoroacetyl, 2- (trimethylsilyl) ethoxycarbonyl, 2-tri Chill silyl ethyl, triphenylmethyl, 2-but the like (triphenylphosphonio) ethoxycarbonyl, but is not limited thereto.

  An explanation of protecting groups is given in Green et al. (T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York (1999)).

The following abbreviations have the meanings given below. ADDP means 1,1 ′-(azodicarbonyl) dipiperidine; AD-mix-β means a mixture of (DHQD) ₂ PHAL, K ₃ Fe (CN) ₆ , K ₂ CO ₃ and K ₂ SO ₄ ) Means 9-BBN means 9-borabicyclo (3.3.1) nonane; (DHQD) ₂ PHAL means hydroquinidine 1,4-phthalazinediyldiethyl ether; DBU means 1,8- Diazabicyclo (5.4.0) undec-7-ene; DIBAL means dibutylaluminum dihydride; DIEA means diisopropylethylamine; DMAP means N, N-dimethylaminopyridine; DMF Means N, N-dimethylformamide; dmpe means 1,2-bis (dimethylphosphino) ethane; DMSO is di Dppb means 1,4-bis (diphenylphosphino) butane; dpppe means 1,2-bis (diphenylphosphino) ethane; dppf means 1,1′-bis (diphenyl) Means phosphino) ferrocene; d means 1,1-bis (diphenylphosphino) methane; EDAC means 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide; Fmoc means fluorenyl HATU means O- (7-azabenzotriazol-1-yl) -N, N'N'N'-tetramethyluronium hexafluorophosphate; HMPA means hexamethylphosphoramide It refers to; IPA means isopropyl alcohol; MP-BH ₃ is macroporous borohydride shear Means triethylammonium methylpolystyrene; PyBOP means benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate; TEA means triethylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran NCS means N-chlorosuccinic acid; NMM means N-methylmorpholine; NMP means N-methylpyrrolidine; PPh ₃ means triphenylphosphine.

  As shown in Scheme 1, the compound of formula (1) is reacted with sodium nitrate and aqueous acid, followed by addition of aqueous sodium acetate and the appropriate 2-oxocycloalkyl ester to give the compound of formula (2) Can be converted to

  Examples of acids include hydrochloric acid.

  Examples of suitable 2-oxocycloalkyl esters include ethyl 2-oxocyclohexanecarboxylate, ethyl 2-oxocyclopentanecarboxylate, and the like.

  The reaction is first carried out at about 0 ° C. over a period of about 30 minutes to about 1 hour, and then is heated from about 15 ° C. to 25 ° C. in water for about 1 to 4 hours.

  A compound of formula (2) can be converted to a compound of formula (3) by reacting it with a borane solution.

  The reaction is typically performed at room temperature for about 8 hours to about 20 hours in a solvent such as but not limited to THF.

A compound of formula (3) can be converted to a compound of formula (4) by reacting it with a reagent such as but not limited to R ⁵ OH, triphenylphosphine and DEAD or TBAD. Can do.

  The addition is typically performed at room temperature or lower, and then allowed to warm to room temperature in a solvent such as but not limited to THF for about 8 to 72 hours.

Introduction of the moiety represented by D ¹ , E ¹ and F ¹ can be carried out by reacting the substituted aniline of formula (1) according to the method shown in scheme (1). Alternatively, the bromoaniline of formula (1) is reacted according to the method shown in scheme (1), and then the literature (Palladium Reagents And Catalysts: New Perspectives For The 21st Century, By J. Tsuji, John Wiley & Sons, Ltd., Chichester, 2004, 1-670) and can be reacted using methods known to those skilled in the art of palladium-catalyzed carbon cross-coupling reactions.

As shown in Scheme 2, the compound of formula (4) can be reacted with a base and then the appropriate compound of formula B ¹ Br (5a) or B ¹ Cl (5b) to give a compound of formula (5) Can be converted to

  Examples of bases include sodium hydride, potassium carbonate and the like.

  Examples of suitable compounds of formula (5a) include 1- (3-bromopropoxy) naphthalene.

  Examples of suitable compounds of formula (5b) include 2-chloro-1-morpholinoethanone.

  The reaction is typically performed at room temperature or lower for about 15 minutes to 1 hour with the addition of a base and then in a solvent such as (but not limited to) DMF or the formula (5a) or After adding the compound of (5b), it is carried out at about 20 ° C. to 80 ° C. for about 1 to 8 hours.

  A compound of formula (5) can be converted to a compound of formula (6) by reacting it with a base.

  Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.

  The reaction is typically carried out in a solvent such as water, methanol, ethanol, isopropanol, or mixtures thereof at about 0 ° C. to 35 ° C. for about 1 hour to about 48 hours.

A compound of formula (4) wherein B ¹ is H can be converted to formula (6) by reacting it with a base.

  Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.

  The reaction is typically carried out in a solvent such as water, methanol, ethanol, isopropanol, or mixtures thereof at about 0 ° C. to 35 ° C. for about 1 hour to about 48 hours.

  As shown in Scheme 3, a compound of formula (3) can be converted to a compound of formula (7) by reacting it with a base and then methanesulfonyl chloride.

  Examples of bases include TEA, pyridine and the like.

  The reaction is typically carried out in acetonitrile at about 0 ° C. to 20 ° C. for about 30 minutes to about 3 hours.

A compound of formula (7) can be converted to a compound of formula (8) by reacting it with a compound of formula R ⁵ SH and a base.

  Examples of bases include potassium carbonate and sodium carbonate.

  The reaction is typically performed in a solvent such as but not limited to acetonitrile at about 50 ° C. to 100 ° C. for 1 to 5 days.

  The compound of formula (8) can be converted to the compound of formula (9) according to the method described in Scheme 2 for the conversion of the compound of formula (4) to the compound of formula (6).

  As shown in Scheme 4, the compound of formula (10) can be reacted with a compound of formula (11), triphenylphosphine and reagents such as but not limited to DEAD or TBAD. Can be converted to a compound of formula (12).

  The addition can be performed at room temperature or lower, and then heated to a room temperature in a solvent such as THF (but not limited to) to allow about 8 to 72 hours.

  As shown in Scheme 5, the compound of formula (12) can be converted to the compound of formula (14) by reacting the compound, the compound of formula (13) and the base.

  Examples of bases include sodium hydride and potassium carbonate.

  The reaction is typically performed at room temperature or lower for about 15 minutes to 1 hour with the addition of a base, and then in a solvent such as (but not limited to) DMF of formula (13). After the compound is added, it is carried out at about 20 ° C. to 80 ° C. for about 1 to 8 hours.

  Compounds of formula (14) are described in the literature (Palladium Reagents And Catalysts: New Perspectives For The 21st Century, By J. Tsuji, John Wiley & Sons, Ltd ,, Chichester, 2004, 1-670). Those skilled in the art of cross-coupling reactions can be converted to compounds of formula (15) using methods known to those skilled in the art.

  The compound of formula (15) can be converted to the compound of formula (16) according to the method described in Scheme 2 for the conversion of the compound of formula (4) to the compound of formula (6).

  As shown in Scheme 6, a compound of formula (3) can be converted to a compound of formula (16) by reacting the compound, iodine, triphenylphosphine and imidazole, and then reacting with a base. it can.

  Examples of bases include sodium carbonate.

  The reaction is typically carried out in a solvent such as but not limited to dichloromethane at about −10 ° C. to about 10 ° C. for about 15 minutes to 1 hour, and then for another 30 minutes after the base addition. Continue for 1 hour.

  The compound of formula (16) can be converted to the compound of formula (17) by reacting the compound with triphenylphosphine.

  The reaction is typically carried out in a solvent such as but not limited to acetonitrile or dichloromethane at reflux for about 8 to about 48 hours.

A compound of formula (17) can be converted to a compound of formula (18) by reacting the compound, a base and a compound of formula R ⁵ C (O) H.

  Examples of bases include sodium hydride and n-butyllithium.

The reaction is first carried out at about 60 ° C. to about 100 ° C. for about 1 hour after the base addition, then cooled to about 10 ° C. to about 25 ° C. and treated with a compound of formula (17). After about 10 to about 20 minutes, a compound of formula R ⁵ C (O) H is added and the mixture is again heated at about 60 ° C. to about 100 ° C. for about 1 to 8 hours.

  A compound of formula (18) can be converted to a compound of formula (19) by reacting the compound with a hydrogen source and a catalyst.

  Examples of the hydrogen source include hydrazine and hydrogen gas.

  Examples of catalysts include Pd / C and Raney nickel.

  The temperature and pressure will vary depending on the hydrogenation method and substrate used. Typical solvents include methanol, ethanol, ethyl acetate and the like.

  The compound of formula (19) can be converted to the compound of formula (20) according to the method described in Scheme 2 for the conversion of the compound of formula (4) to the compound of formula (6).

  As shown in Scheme 7, the compound of formula (3) can be converted to the compound of formula (21) by reacting the compound, DMSO, base and dehydrating agent.

  Examples of bases include triethylamine, diisopropylamine and the like.

  Examples of dehydrating agents include oxalyl chloride, trifluoroacetic anhydride and pyridine sulfate.

  The reaction is typically conducted at about −60 ° C. to about 0 ° C. for about 1 hour to about 8 hours, depending on the substrate and method used.

  The following examples are provided to give what is believed to be the most useful and understandable explanation for the procedures and conceptual aspects of the present invention.

Example 1
3- (3-Cyclohexylpropyl) -1H-indole-2-carboxylic acid

(Example 2)
3- (4-Cyclohexylbutyl) -1H-indole-2-carboxylic acid

(Example 3A)
Ethyl 3- (3-hydroxypropyl) -1H-indole-2-carboxylate Ethyl 3- (3-ethoxy-3-oxopropyl) -1H-indole-2-carboxylate (2.82 g) in THF (40 mL) To the medium mixture was added 1M borane.THF (40 mL). The mixture was stirred at room temperature for 16 hours, quenched with methanol (100 mL) and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% to 25% ethyl acetate / hexane.

(Example 3B)
3- (3- (3-Chlorophenoxy) propyl) -1H-indole-2-carboxylate ethyl 3-chlorophenol (0.050 g), Example 3A (0.052 g), di-tert-butyl azodicarboxylate A mixture of (0.086 g) and triphenylphosphine (0.1 g) in THF (2.5 mL) was stirred at room temperature for 24 hours and concentrated. The concentrate was purified by reverse phase HPLC (Zorbax SB, C-18, 30% to 100% acetonitrile / water / 0.1% trifluoroacetic acid).

(Example 3C)
3- (3- (3-Chlorophenoxy) propyl) -1H-indole-2-carboxylic acid A mixture of Example 3B (0.035 mg) and LiOH (0.1 g) in methanol / water (1: 1, 5 mL). Was heated at 150 ° C. for 10 minutes under microwave (CEM Discover) conditions (70 W). The reaction mixture was concentrated, diluted with water (2 mL), treated with 5M HCl and extracted with ethyl acetate. The extract was dried (Na ₂ SO ₄ ), filtered and concentrated. The concentrate was purified by reverse phase HPLC (Zorbax SB, C-18, 20% to 100% acetonitrile / water / 0.1% trifluoroacetic acid). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.88 (brs, 1H), 11.40 (s, 1H), 7.63 (d, 1H), 7.39 (d, 1H), 7.24 (M, 2H), 6.92 (m, 4H), 3.97 (t, 2H), 3.20 (t, 2H), 2.05 (m, 2H).

(Example 4A)
3- (3- (3- (3- (trifluoromethyl) phenoxy) propyl) -1H-indole-2-carboxylate in Example 3B substituting 3- (trifluoromethyl) phenol for 3-chlorophenol This example was manufactured.

(Example 4B)
3- (3- (3- (Trifluoromethyl) phenoxy) propyl) -1H-indole-2-carboxylic acid This example was prepared by substituting Example 4A for Example 3C instead of Example 3B. . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.88 (brs, 1H), 11.40 (s, 1H), 7.63 (d, 1H), 7.49 (t, 1H), 7.39 (D, 1H), 7.22 (m, 4H), 6.98 (t, 1H), 4.04 (t, 2H), 3.21 (t, 2H), 2.07 (m, 2H) .

(Example 5A)
Ethyl 3- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate This example was prepared by substituting 1-naphthol for 3-chlorophenol in Example 3B.

(Example 5B)
3- (3- (Naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylic acid This example was prepared by substituting Example 5A for Example 3C in Example 3C. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.96 (brs, 1H), 11.44 (s, 1H), 8.24 (d, 1H), 7.86 (d, 1H), 7.66 (D, 1H), 7.52 (m, 2H), 7.41 (m, 3H), 7.21 (t, 1H), 6.96 (t, 1H), 6.87 (d, 1H) 4.16 (t, 2H), 3.33 (m, 2H), 2.20 (m, 2H).

(Example 6A)
Ethyl 3- (3- (2-benzylphenoxy) propyl) -1H-indole-2-carboxylate This example was prepared by substituting 2-benzylphenol for 3-chlorophenol in Example 3B.

(Example 6B)
3- (3- (2-Benzylphenoxy) propyl) -1H-indole-2-carboxylic acid This example was prepared by substituting Example 6A for Example 3C instead of Example 3B. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.92 (brs, 1H), 11.40 (s, 1H), 7.50 (d, 1H), 7.38 (d, 1H), 7.22 (M, 5H), 7.13 (m, 3H), 6.95 (t, 1H), 6.85 (m, 2H), 3.95 (m, 4H), 3.18 (t, 2H) 2.04 (m, 2H).

(Example 7A)
Ethyl 3- (3- (2,3-dihydro-1H-inden-5-yloxy) propyl) -1H-indole-2-carboxylate 2,3-dihydro-1H instead of 3-chlorophenol in Example 3B -This example was prepared by using inden-5-ol.

(Example 7B)
3- (3- (2,3-Dihydro-1H-inden-5-yloxy) propyl) -1H-indole-2-carboxylic acid This example was obtained by substituting Example 7A for Example 3C in Example 3C. Examples were prepared. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.90 (brs, 1H), 11.41 (s, 1H), 7.63 (d, 1H), 7.39 (d, 1H), 7.21 (T, 1H), 7.07 (d, 1H), 7.00 (t, 1H), 6.74 (s, 1H), 6.64 (dd, 1H), 3.90 (t, 2H) 3.19 (t, 2H), 2.77 (m, 4H), 2.00 (m, 4H).

(Example 8A)
3- (3- (3-Methylnaphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate in Example 3B by using 3-methylnaphthalen-1-ol instead of 3-chlorophenol This example was manufactured.

(Example 8B)
3- (3- (3-Methylnaphthalen-1-yloxy) propyl) -1H-indole-2-carboxylic acid This example was prepared by substituting Example 8A for Example 3C in Example 3C. . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.91 (brs, 1H), 11.43 (s, 1H), 8.00 (d, 1H), 7.86 (d, 1H), 7.71 (D, 1H), 7.59 (d, 1H), 7.44 (m, 3H), 7.34 (d, 1H), 7.24 (t, 1H), 7.05 (t, 1H) 3.97 (t, 2H), 2.37 (s, 3H), 2.21 (m, 2H).

(Example 9A)
3- (3- (2-Methylnaphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate in Example 3B by using 2-methylnaphthalen-1-ol instead of 3-chlorophenol This example was manufactured.

(Example 9B)
3- (3-((2-Methyl-1-naphthyl) oxy) propyl) -1H-indole-2-carboxylic acid This example was obtained by substituting Example 9A for Example 3C in Example 3C. Manufactured. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.89 (brs, 1H), 11.4 (s, 1H), 8.00 (d, 1H), 7.86 (d, 1H), 7.70 (D, 1H), 7.59 (d, 1H), 7.45 (m, 3H), 7.34 (d, 1H), 7.5 (m, 1H), 7.05 (t, 1H) 3.97 (t, 2H), 2.37 (s, 3H), 2.15-2.26 (m, 2H).

(Example 10A)
Ethyl 3- (3- (methylsulfonyloxy) propyl) -1H-indole-2-carboxylate To a mixture of Example 3A (0.125 g) and triethylamine (0.21 mL) in acetonitrile (3 mL) at 0-5 ° C. , Methanesulfonyl chloride (0.0404 mL) was added. After 30 minutes, the mixture was concentrated and the concentrate was purified by flash chromatography on silica gel with 0-30% ethyl acetate / hexane.

(Example 10B)
Ethyl 3- (3- (naphthalen-1-ylthio) propyl) -1H-indole-2-carboxylate A mixture of Example 10A (42 mg), naphthalenethiol (45 mg) and potassium carbonate (36 mg) in acetonitrile (2 mL). And heated at 80 ° C. for 3 days. The reaction mixture was poured into water, extracted with dichloromethane, and purified by flash chromatography on silica gel using 0-20% ethyl acetate / hexane.

(Example 10C)
3- (3- (1-Naphtylthio) propyl) -1H-indole-2-carboxylic acid This example was prepared by substituting Example 10B for Example 3B in Example 3C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.92 (s, 1H), 11.42 (s, 1H), 8.11-8.32 (m, 1H), 7.85-8.03 ( m, 1H), 7.77 (d, 1H), 7.50-7.67 (m, 2H), 7.32-7.50 (m, 2H), 7.21 (t, 1H), 6 .98 (t, 1H), 3.12-3.26 (m, 2H), 3.06 (t, 2H), 1.85-2.05 (m, 2H).

(Example 11A)
Ethyl 5-bromo-3- (3-ethoxy-3-oxopropyl) -1H-indole-2-carboxylate 4-bromoaniline (3.44 g) in 5M aqueous HCl (12 mL) at 0 ° C. 0.5M NaNO ₂ (1.38 g) / water (20 mL) was added. After the addition, 4.5 M sodium acetate (9.23 g) / water (25 mL) was added, followed by 2-oxo-cyclopentanecarboxylic acid ethyl ester (3 mL). The mixture was stirred at 0 ° C. for 15 minutes, warmed to 19 ° C. over 2 hours and extracted with dichloromethane. The extract was dried (MgSO ₄ ), filtered and concentrated. The concentrate was dissolved in 10% H ₂ SO ₄ / ethanol (22 mL), refluxed overnight, cooled to room temperature, quenched with water (0.4 liter) and filtered.

(Example 11B)
Ethyl 5-bromo-3- (3-hydroxypropyl) -1H-indole-2-carboxylate In Example 3A, instead of ethyl 3- (3-ethoxy-3-oxopropyl) -1H-indole-2-carboxylate Example 11A was used to make this example.

(Example 11C)
Ethyl 5-bromo- (3- (3- (3-naphthalen-1-yloxy) propyl))-1H-indole-2-carboxylate Example 3A substituting 1-naphthol for 3-chlorophenol in Example 3B This example was prepared by using Example 11B instead.

(Example 11D)
5-Bromo- (3- (3- (3-phthalen-1-yloxy) propyl))-1H-indole-2-carboxylic acid This example was obtained by substituting Example 11C for Example 3C in Example 3C. Manufactured. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.14 (brs, 1H), 11.63 (s, 1H), 8.23 (m, 1H), 7.85 (m, 2H), 7.49 (M, 3H), 7.33 (m, 3H), 6.86 (d, 1H), 4.15 (t, 2H), 2.19 (m, 2H).

(Example 12)
3- (3- (1-Naphtyloxy) propyl) -5-((1E) -3-phenylprop-1-enyl) -1H-indole-2-carboxylic acid Example 11C (45.2 mg), (E ) -3-Phenylprop-1-enylboronic acid (21.1 mg), bis (triphenylphosphine) palladium (II) dichloride (catalytic amount) and 2M LiOH (0.3 mL) 7/2/3 dimethoxyethane / ethanol The mixture in / H ₂ O (2 mL) was heated at 150 ° C. for 30 minutes under microwave (CEM Discover) conditions. The mixture was quenched with 1M HCl (0.4 mL) and extracted with ethyl acetate. The extract was dried (MgSO ₄ ), filtered and concentrated. The concentrate was purified by reverse phase HPLC (Zorbax SB-C18, 20% to 100% acetonitrile / water / 0.1% trifluoroacetic acid). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.95 (brs, 1H), 11.44 (s, 1H), 8.34 (d, 1H), 7.88 (d, 1H), 7.54 (M, 2H), 7.44 (m, 2H), 7.31 (m, 5H), 7.18 (m, 3H), 6.83 (d, 1H), 6.00 (m, 2H) 4.08 (t, 2H), 2.21 (m, 2H).

(Example 13)
5-((E) -2-cyclohexylvinyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid In Example 12, (E) -3-phenylprop-1- This example was prepared by using (E) -2-cyclohexylvinylboronic acid instead of enylboronic acid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.95 (brs, 1H), 11.42 (s, 1H), 8.36 (m, 1H), 7.88 (m, 1H), 7.56 (M, 2H), 7.43 (m, 2H), 7.34 (m, 1H), 7.26 (m, 2H), 6.81 (d, 1H), 5.80 (m, 2H) 4.07 (t, 2H), 2.21 (t, 2H), 1.85 (m, 1H), 1.62 (m, 5H), 1.20 (m, 3H), 0.92 ( m, 2H).

(Example 14)
3- (3- (1-Naphtyloxy) propyl) -5-((E) -2-phenylvinyl) -1H-indole-2-carboxylic acid In Example 12, (E) -3-phenylprop-1- This example was prepared by using (E) -styrylboronic acid instead of enylboronic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (brs, 1H), 11.56 (s, 1H), 8.39 (m, 1H), 7.92 (m, 1H), 7.58 (M, 4H), 7.43 (d, 1H), 7.28 (m, 7H), 6.92 (d, 1H), 6.84 (d, 1H), 6.68 (d, 1H) 4.10 (t, 2H), 3.39 (t, 2H), 2.25 (m, 2H).

(Example 15)
5- (4-Fluorophenyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid Instead of (E) -3-phenylprop-1-enylboronic acid in Example 12 This example was prepared using 4-fluoro-phenylboronic acid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.05 (brs, 1H), 11.56 (s, 1H), 8.33 (d, 1H), 7.92 (d, 1H), 7.71 (S, 1H), 7.50 (m, 5H), 7.35 (t, 1H), 7.20 (m, 2H), 6.96 (m, 2H), 6.85 (d, 1H) 4.11 (t, 2H), 3.40 (t, 2H), 2.25 (m, 2H).

(Example 16)
3- (3- (1-Naphtyloxy) propyl) -5- (2-phenylethyl) -1H-indole-2-carboxylic acid Example 14 (0.005 g), cyclohexene (0.5 mL), Pd / C A mixture of (catalytic amount) in ethanol (4 mL) was heated at 130 ° C. (270 W) in a microwave (CEM Discover) for 10 minutes. The reaction mixture was filtered and the filtrate was concentrated. The concentrate was purified by preparative reverse phase HPLC (Zorbax SB, C-18, 20% to 100% acetonitrile / water / 0.1% trifluoroacetic acid) to give the title compound. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.88 (brs, 1H), 11.32 (s, 1H), 8.34 (m, 1H), 7.84 (m, 1H), 7.53 (M, 2H), 7.42 (d, 1H), 7.34 (m, 2H), 7.23 (m, 3H), 7.13 (m, 1H), 7.01 (m, 3H) 6.84 (d, 1H), 4.08 (t, 2H), 2.56 (s, 4H), 2.19 (m, 2H).

(Example 17)
3- (3-((7-Methyl-2,3-dihydro-1H-inden-4-yl) oxy) propyl) -1H-indole-2-carboxylic acid

(Example 17A)
This example was prepared by using 7-methyl-2,3-dihydro-1H-inden-4-ol instead of 3-chlorophenol in Example 3B.

(Example 17B)
3- (3-((7-Methyl-2,3-dihydro-1H-inden-4-yl) oxy) propyl) -1H-indole-2-carboxylic acid Example 3C instead of Example 3B This example was manufactured by using 17A. ¹ H NMR (500 MHz, chloroform-d) δ 8.72 (s, 1H), 7.73 (d, 1H), 7.36 (m, 2H), 7.14 (t, 1H), 6.87 ( d, 1H), 6.55 (d, 1H), 4.03 (t, 2H), 3.34 (t, 2H), 2.95 (t, 2H), 2.84 (t, 2H), 2.19 (m, 5H), 2.09 (m, 2H).

(Example 18A)
Ethyl 3- (3- (5,6,7,8-tetrahydronaphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate 5,6,7, in place of 3-chlorophenol in Example 3B This example was prepared by using 8-tetrahydronaphthalen-1-ol.

(Example 18B)
3- (3- (5,6,7,8-tetrahydronaphthalen-1-yloxy) propyl) -1H-indole-2-carboxylic acid Example 18A was used in place of Example 3B in Example 3C. This example was manufactured. ¹ H NMR (500 MHz, chloroform-d) δ 8.75 (s, 1H), 7.73 (d, 1H), 7.38 (m, 2H), 7.14 (t, 1H), 7.01 ( t, 1H), 6.68 (d, 1H), 6.60 (d, 1H), 4.03 (t, 2H), 3.37 (t, 2H), 2.76 (m, 4H), 2.22 (m, 2H), 1.80 (m, 4H).

(Example 19A)
Ethyl 4-bromo-3- (3-ethoxy-3-oxopropyl) -1H-indole-2-carboxylate This example was obtained by substituting 3-bromoaniline for 4-bromoaniline in Example 11A. Manufactured.

(Example 19B)
4-Bromo-3- (3-hydroxypropyl) -1H-indole-2-carboxylate in Example 3A instead of ethyl 3- (3-ethoxy-3-oxopropyl) -1H-indole-2-carboxylate Example 19A was used to make this example.

(Example 19C)
4-Bromo- (3- (3- (3- (naphthalen-1-yloxy) propyl))-1H-indole-2-carboxylate Example 3A substituting 1-naphthol for 3-chlorophenol in Example 3B This example was prepared by using Example 19B instead.

(Example 19D)
4- (4-Fluorophenyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid Instead of (E) -3-phenylprop-1-enylboronic acid in Example 12 This example was prepared using 4-fluoro-phenylboronic acid and substituting Example 19C for Example 11C. ¹ H NMR (500 MHz, chloroform-d) δ 8.76 (s, 1H), 7.73 (d, 1H), 7.38 (m, 2H), 7.14 (t, 1H), 7.02 ( t, 1H), 6.68 (d, 1H), 6.59 (d, 1H), 4.02 (t, 2H), 3.37 (t, 2H), 2.75 (m, 4H), 2.22 (m, 2H), 1.80 (m, 4H).

(Example 20A)
Ethyl 6-bromo-3- (3-ethoxy-3-oxopropyl) -1H-indole-2-carboxylate This example was obtained by substituting 3-bromoaniline for 4-bromoaniline in Example 11A. Manufactured.

(Example 20B)
Ethyl 6-bromo-3- (3-hydroxypropyl) -1H-indole-2-carboxylate Instead of ethyl 3- (3-ethoxy-3-oxopropyl) -1H-indole-2-carboxylate in Example 3A Example 20A was used to make this example.

(Example 20C)
Ethyl 6-bromo- (3- (3- (3- (naphthalen-1-yloxy) propyl))-1H-indole-2-carboxylate Example 3A substituting 1-naphthol for 3-chlorophenol in Example 3B This example was produced by using Example 20B instead of.

(Example 20D)
3- (3- (1-Naphtyloxy) propyl) -6-((E) -2-phenylvinyl) -1H-indole-2-carboxylic acid In Example 12, (E) -3-phenylprop-1- This example was prepared by using (E) -styrylboronic acid instead of enylboronic acid and Example 20C instead of Example 11C. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.98 (brs, 1H), 11.53 (s, 1H), 8.24 (m, 1H), 7.86 (m, 1H), 7.64 (M, 3H), 7.53 (m, 3H), 7.45 (m, 1H), 7.36 (m, 5H), 7.21 (m, 2H), 6.88 (d, 1H) 4.17 (t, 2H), 2.21 (m, 2H).

(Example 21)
3- (3- (1-Naphtyloxy) propyl) -6-((1E) -3-phenylprop-1-enyl) -1H-indole-2-carboxylic acid Performed in place of Example 11C in Example 12 This example was prepared using Example 20C. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.94 (brs, 1H), 11.39 (s, 1H), 8.21 (d, 1H), 7.86 (d, 1H), 7.54 (M, 3H), 7.44 (m, 1H), 7.32 (m, 6H), 7.21 (m, 1H), 7.12 (d, 1H), 6.87 (d, 1H) 6.55 (d, 1H), 6.37 (m, 1H), 4.14 (t, 2H), 3.54 (d, 2H), 2.19 (m, 2H).

(Example 22)
3- (3- (1-Naphtyloxy) propyl) -4-((1E) -3-phenylprop-1-enyl) -1H-indole-2-carboxylic acid Performed instead of Example 11C in Example 12 This example was prepared using Example 19C. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.01 (brs, 1H), 11.49 (s, 1H), 8.19 (m, 1H), 7.81 (m, 1H), 7.33 (M, 13H), 6.91 (d, 1H), 6.32 (m, 1H), 4.14 (t, 2H), 3.55 (m, 2H), 3.45 (m, 2H) 2.12 (m, 2H).

(Example 23)
6- (3- (Benzyloxy) phenyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid In Example 12, (E) -3-phenylprop-1-enylboron This example was made by substituting 3- (benzyloxy) -phenylboronic acid for the acid and using Example 20C for the Example 11C. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.03 (s, 1H), 11.52 (s, 1H), 8.24 (m, 1H), 7.86 (s, 1H), 7.73 (D, 1H), 7.60 (s, 1H), 7.35 (m, 13H), 7.01 (m, 1H), 6.88 (d, 1H), 5.18 (s, 2H) 4.18 (t, 2H), 2.24 (m, 2H).

(Example 24)
4- (3- (Benzyloxy) phenyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid In Example 12, (E) -3-phenylprop-1-enylboron This example was prepared by substituting 3- (benzyloxy) -phenylboronic acid for the acid and using Example 19C for the Example 11C. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.98 (brs, 1H), 11.62 (s, 1H), 8.03 (d, 1H), 7.83 (d, 1H), 7.47 (M, 4H), 7.34 (m, 4H), 7.24 (m, 4H), 7.03 (m, 3H), 6.83 (d, 1H), 6.70 (d, 1H) 5.07 (s, 2H), 3.65 (m, 2H), 2.84 (m, 2H), 1.72 (m, 2H).

(Example 25A)
Ethyl 5-bromo-3- (4-ethoxy-4-oxobutyl) -1H-indole-2-carboxylate In Example 11A, use ethyl 2-oxocyclohexanecarboxylate instead of ethyl 2-oxocyclopentanecarboxylate. Thus, this example was manufactured.

(Example 25B)
Ethyl 5-bromo-3- (4-hydroxybutyl) -1H-indole-2-carboxylate In Example 3A, instead of ethyl 3- (3-ethoxy-3-oxopropyl) -1H-indole-2-carboxylate Example 25A was used to make this example.

(Example 25C)
Ethyl 5-bromo-3- (4- (naphthalen-1-yloxy) butyl) -1H-indole-2-carboxylate In Example 3B, 1-naphthol was used instead of 3-chlorophenol, and Example 3A was used instead. Example 25B was used to make this example.

(Example 25D)
5-Bromo-3- (4- (1-naphthyloxy) butyl) -1H-indole-2-carboxylic acid This example was prepared by substituting Example 25C for Example 3C instead of Example 3B. . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.11 (brs, 1H), 11.61 (s, 1H), 8.09 (d, 1H), 7.89 (s, 1H), 7.84 (D, 1H), 7.47 (m, 3H), 7.36 (m, 3H), 6.93 (d, 1H), 4.16 (m, 2H), 3.16 (m, 2H) 1.88 (m, 4H).

(Example 26A)
To a mixture of NaH (20 mg) in 60% oil in 1-methyl-3- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate in DMF (5 mL) was added Example 5A (0 0.1 g) was added. After stirring at room temperature for 30 minutes, CH ₃ I (0.1 mL) was added and the mixture was stirred for 16 hours. Water and dichloromethane were added to the mixture and the extract was separated and concentrated.

(Example 26B)
1-Methyl-3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid This example was prepared by substituting Example 26A for Example 3C in Example 3C. . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.12 (brs, 1H), 8.20 (d, 1H), 7.86 (d, 1H), 7.69 (d, 1H), 7.52 (M, 3H), 7.44 (d, 1H), 7.37 (t, 1H), 7.30 (t, 1H), 7.00 (t, 1H), 6.87 (d, 1H) 4.15 (t, 2H), 3.96 (s, 3H), 2.19 (m, 2H).

(Example 27)
3- (3- (1-naphthyloxy) propyl) -6-phenyl-1H-indole-2-carboxylic acid In Example 12, instead of (E) -3-phenylprop-1-enylboronic acid, phenylboronic acid was used. This example was prepared by using Example 20C instead of Example 11C. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.00 (brs, 1H), 11.65 (s, 1H), 8.01 (d, 1H), 7.83 (d, 1H), 7.43 (M, 10H), 7.28 (m, 1H), 6.83 (d, 1H), 6.70 (d, 1H), 3.65 (t, 2H), 2.88 (m, 2H) 1.67 (m, 2H).

(Example 28)
6- (2-Methylphenyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid Instead of (E) -3-phenylprop-1-enylboronic acid in Example 12 This example was prepared using 2-methylphenylboronic acid and using Example 20C instead of Example 11C. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.97 (brs, 1H), 11.62 (s, 1H), 8.03 (d, 1H), 7.83 (d, 1H), 7.37 (M, 10H), 6.72 (m, 2H), 3.60 (m, 2H), 2.91 (m, 1H), 2.42 (m, 1H), 1.99 (s, 3H) 1.66 (m, 2H).

(Example 29)
6- (3-Methylphenyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid In Example 12, instead of (E) -3-phenylprop-1-enylboronic acid This example was prepared using 3-methylphenylboronic acid and using Example 20C instead of Example 11C. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.99 (brs, 1H), 11.64 (s, 1H), 8.01 (d, 1H), 7.83 (d, 1H), 7.35 (M, 10H), 6.82 (d, 1H), 6.72 (d, 1H), 3.67 (m, 2H), 2.85 (m, 2H), 2.30 (s, 3H) 1.74 (m, 2H).

(Example 30)
6- (4-Methylphenyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid Instead of (E) -3-phenylprop-1-enylboronic acid in Example 12 This example was prepared by using 4-methylphenylboronic acid and using Example 20C instead of Example 11C. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.98 (s, 1H), 11.61 (s, 1H), 8.00 (d, 1H), 7.83 (d, 1H), 7.36 (M, 10H), 6.80 (d, 1H), 6.70 (d, 1H), 3.63 (t, 2H), 2.90 (m, 2H), 2.29 (s, 3H) 1.69 (m, 2H).

(Example 31A)
1- (3-bromopropoxy) naphthalene 1-naphthol (3.45 g), 3-bromopropanol (1.75 mL), di-t-butyl azo-dicarboxylate (5.52 g) and triphenylphosphine (6.28 g) ) In THF (30 mL) was stirred at room temperature for 16 h and concentrated. The concentrate was diluted with ethyl acetate, washed with water and brine, dried (MgSO ₄ ), filtered and concentrated. The concentrate was purified by silica gel chromatography using 0-7% ethyl acetate / hexane.

(Example 31B)
Ethyl 3-bromo-1H-indole-2-carboxylate A mixture of ethyl 2-indolecarboxylate (1.89 g) and N-bromosuccinic acid (1.77 g) in THF (30 mL) was stirred at room temperature for 1 hour. The mixture was poured into water (150 mL) and filtered. The filtrate was washed with THF, vacuum dried at 60 ° C., and recrystallized from ethyl acetate / hexane.

(Example 31C)
To a mixture of ethyl 3-bromo-1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate NaH (0.112 g) in DMF (5 mL) was added Example 31B (0.58 g). ) Was added. The mixture was stirred for 30 minutes, treated with Example 31A (0.532 g) in DMF (3 mL), stirred at 80 ° C. for 1 hour, quenched with saturated NH ₄ Cl, and extracted with ethyl acetate. The extract was washed with water and brine, dried (MgSO ₄ ), filtered and concentrated. The concentrate was purified by silica gel chromatography using 0-7% ethyl acetate / hexane.

(Example 31D)
Ethyl 1- (3- (naphthalen-1-yloxy) propyl) -3-ortho-tolyl-1H-indole-2-carboxylate Example 31C (90 mg), ortho-toluboronic acid (54 mg), tris (dibenzylideneacetone) ) A mixture of dipalladium (0) (18 mg), tri-tert-butylphosphine tetrafluoroborate (5.8 mg), CsF (90 mg) in THF (2 mL) was stirred at room temperature for 16 hours and diluted with ethyl acetate. , Washed with water and brine. The combined extracts were dried (MgSO ₄ ), filtered and concentrated.

(Example 31E)
3- (2-Methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid A mixture of Example 31D in 1N LiOH: dioxane (0.5 mL: 2 mL) was micronized. Heated at 130 ° C. for 30 minutes under wave conditions (CEM Discover). The mixture was quenched with 1N HCl aqueous mixture (0.5 mL) and extracted with ethyl acetate. The extract was dried (Na ₂ SO ₄ ), filtered and concentrated. The concentrate was purified by reverse phase HPLC (Zorbax SB-C18, 20% to 100% acetonitrile / water / 0.1% trifluoroacetic acid). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.73 (bs, 1H), 8.23 (d, 1H), 7.87 (d, 1H), 7.66 (d, 1H), 7.52 (M, 3H), 7.38 (t, 1H), 7.26 (m, 4H), 7.12 (m, 2H), 7.04 (m, 1H), 6.87 (d, 2H) 4.91 (t, 2H), 4.19 (t, 2H), 2.38 (m, 2H), 2.01 (s, 3H).

(Example 32A)
3- (Naphthalen-1-yl) -1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate 1-Naphthaleneboronic acid instead of ortho-tolylboronic acid in Example 31D This example was manufactured by using

(Example 32B)
3- (1-Naphthyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid This example was obtained by substituting Example 32A for Example 31E in Example 31E. An example was manufactured. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.61 (bs, 1H), 8.22 (d, 1H), 7.96 (m, 2H), 7.87 (d, 1H), 7.74 (D, 1H), 7.48 (m, 8H), 7.31 (m, 1H), 7.25 (m, 1H), 7.02 (m, 2H), 6.91 (d, 1H) 4.98 (t, 2H), 4.25 (t, 2H), 2.45 (m, 2H).

(Example 33A)
Ethyl 3- (3- (3- (dimethylamino) propylcarbamoyl) phenyl) -1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate Ortho-tolylboronic acid in Example 31D This example was prepared by using N- (3- (N ', N'-dimethylamino) propyl) benzamide-3-boronic acid pinacol ester instead of.

(Example 33B)
3- (3-(((3- (Dimethylamino) propyl) amino) carbonyl) phenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid Performed in Example 31E This example was made by using Example 33A instead of Example 31D. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.06 (bs, 1H), 8.64 (t, 1H), 8.25 (d, 1H), 7.93 (s, 1H), 7.86 (M, 2H), 7.70 (d, 1H), 7.53 (m, 5H), 7.39 (m, 2H), 7.27 (m, 1H), 7.11 (m, 1H) 6.89 (d, 1H), 4.89 (t, 2H), 4.20 (t, 2H), 3.10 (t, 2H), 2.78 (s, 6H), 2.38 ( m, 2H), 1.88 (m, 2H).

(Example 34A)
Ethyl 3- (biphenyl-2-yl) -1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate 2-biphenylboronic acid instead of ortho-tolylboronic acid in Example 31D This example was manufactured by using

(Example 34B)
3- (1,1′-biphenyl-2-yl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid Example 34A instead of Example 31D in Example 31E This example was manufactured by using ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.68 (br, 1H), 8.24 (d, 1H), 7.86 (d, 1H), 7.52 (m, 3H), 7.38 (M, 6H), 7.08 (m, 7H), 6.93 (m, 1H), 6.76 (d, 1H), 4.78 (m, 2H), 4.00 (m, 2H) 2.22 (m, 2H).

(Example 35A)
2- (3-Bromopropoxy) naphthalene This example was prepared by substituting 2-naphthol for 1-naphthol in Example 31A.

(Example 35B)
3-Bromo-1- (3- (naphthalen-2-yloxy) propyl) -1H-indole-2-carboxylate This example was obtained by substituting Example 35A for Example 31A in Example 31C. Manufactured.

(Example 35C)
1- (3- (Naphthalen-2-yloxy) propyl) -3-ortho-tolyl-1H-indole-2-carboxylate This example was obtained by substituting Example 35B for Example 31B in Example 31D. An example was manufactured.

(Example 35D)
3- (2-Methylphenyl) -1- (3- (2-naphthyloxy) propyl) -1H-indole-2-carboxylic acid In Example 31E, Example 35C was used instead of Example 31D. Examples were prepared. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.69 (br, 1H), 7.82 (m, 2H), 7.73 (d, 1H), 7.66 (d, 1H), 7.44 (M, 1H), 7.33 (m, 1H), 7.21 (m, 7H), 7.09 (m, 1H), 7.04 (m, 1H), 4.84 (t, 2H) 4.07 (t, 2H), 2.30 (m, 2H), 2.01 (s, 3H).

(Example 36A)
5- (3-Bromopropoxy) -1,2,3,4-tetrahydronaphthalene In this example, 5,6,7,8-tetrahydro-1-naphthol was used instead of 1-naphthol in Example 31A. Manufactured.

(Example 36B)
Ethyl 3-bromo-1- (3- (5,6,7,8-tetrahydronaphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate Example 36A instead of Example 31A in Example 31C This example was manufactured by using

(Example 36C)
Ethyl 1- (3- (5,6,7,8-tetrahydronaphthalen-1-yloxy) propyl) -3-ortho-tolyl-1H-indole-2-carboxylate carried out in place of Example 31C in Example 31D This example was prepared using Example 36B.

(Example 36D)
3- (2-Methylphenyl) -1- (3- (5,6,7,8-tetrahydronaphthalen-1-yloxy) propyl) -1H-indole-2-carboxylic acid Example 31E in place of Example 31D Example 36C was used to make this example. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.69 (br, 1H), 7.62 (d, 1H), 7.29 (m, 4H), 7.09 (m, 3H), 6.98 (M, 1H), 6.64 (m, 2H), 4.79 (t, 2H), 3.96 (t, 2H), 2.68 (m, 2H), 2.61 (t, 2H) 2.23 (m, 2H), 2.02 (s, 3H), 1.71 (m, 4H).

(Example 37A)
1- (3- (Naphthalen-1-yloxy) propyl) -3-m-tolyl-1H-indole-2-carboxylate in Example 31D using m-tolylboronic acid instead of ortho-tolylboronic acid, This example was manufactured.

(Example 37B)
3- (3-Methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid In Example 31E, Example 37A was used instead of Example 31D. Examples were prepared. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.95 (br, 1H), 8.21 (d, 1H), 7.87 (d, 1H), 7.66 (d, 1H), 7.50 (M, 4H), 7.38 (m, 1H), 7.31 (m, 1H), 7.24 (m, 1H), 7.19 (s, 1H), 7.16 (m, 2H) 7.09 (m, 1H), 6.88 (d, 1H), 4.85 (t, 2H), 4.19 (t, 2H), 2.37 (m, 2H), 2.35 ( s, 3H).

(Example 38A)
Ethyl 3- (3-chlorophenyl) -1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate In Example 31D, 3-chlorophenylboronic acid is used instead of ortho-tolylboronic acid. Thus, this example was manufactured.

(Example 38B)
3- (3-Chlorophenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid This example was obtained by substituting Example 38A for Example 31E in Example 31E. An example was manufactured. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.11 (br, 1H), 8.17 (d, 1H), 7.87 (d, 1H), 7.69 (d, 1H), 7.45 (M, 8H), 7.25 (m, 2H), 7.12 (m, 1H), 6.88 (d, 1H), 4.88 (t, 2H), 4.20 (t, 2H) 2.38 (m, 2H).

(Example 39A)
Ethyl 1- (3- (naphthalen-1-yloxy) propyl) -3-phenyl-1H-indole-2-carboxylate In this example, the phenylboronic acid was used in place of ortho-tolylboronic acid in Example 31D. Manufactured.

(Example 39B)
1- (3- (1-Naphtyloxy) propyl) -3-phenyl-1H-indole-2-carboxylic acid This example was prepared by substituting Example 39A for Example 31E in Example 31E. . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.99 (br, 1H), 8.24 (d, 1H), 7.87 (d, 1H), 7.66 (d, 1H), 7.52 (M, 2H), 7.40 (m, 7H), 7.24 (m, 2H), 7.09 (m, 1H), 6.88 (d, 1H), 4.86 (t, 2H) 4.20 (t, 2H), 2.37 (m, 2H).

(Example 40A)
1- (3- (Naphthalen-1-yloxy) propyl) -3- (2- (trifluoromethyl) phenyl) -1H-indole-2-carboxylate in place of ortho-tolylboronic acid in Example 31D This example was prepared by using (trifluoromethyl) phenylboronic acid.

(Example 40B)
1- (3- (1-Naphtyloxy) propyl) -3- (2- (trifluoromethyl) phenyl) -1H-indole-2-carboxylic acid Example 40A is used instead of Example 31D in Example 31E Thus, this example was manufactured. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.75 (br, 1H), 8.24 (d, 1H), 7.87 (d, 1H), 7.82 (d, 1H), 7.69 (M, 2H), 7.60 (m, 1H), 7.52 (m, 3H), 7.36 (m, 2H), 7.24 (m, 1H), 7.06 (m, 2H) 6.88 (d, 1H), 4.92 (t, 2H), 4.17 (t, 2H), 2.36 (m, 2H).

(Example 41A)
1- (3- (Naphthalen-1-yloxy) propyl) -3- (3- (trifluoromethyl) phenyl) -1H-indole-2-carboxylate instead of ortho-tolylboronic acid in Example 31D, 3- This example was prepared by using (trifluoromethyl) phenylboronic acid.

(Example 41B)
1- (3- (1-Naphtyloxy) propyl) -3- (3- (trifluoromethyl) phenyl) -1H-indole-2-carboxylic acid Example 41A is used instead of Example 31D in Example 31E Thus, this example was manufactured. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.13 (br, 1H), 8.16 (d, 1H), 7.87 (d, 1H), 7.70 (m, 5H), 7.48 (M, 3H), 7.38 (m, 2H), 7.28 (m, 1H), 7.13 (m, 1H), 6.88 (d, 1H), 4.90 (t, 2H) 4.21 (t, 2H), 2.39 (m, 2H).

(Example 42A)
Ethyl 1- (3- (naphthalen-1-yloxy) propyl) -3- (4- (trifluoromethyl) phenyl) -1H-indole-2-carboxylate instead of ortho-tolylboronic acid in Example 31D, 4- This example was prepared by using (trifluoromethyl) phenylboronic acid.

(Example 42B)
1- (3- (1-Naphthyloxy) propyl) -3- (4- (trifluoromethyl) phenyl) -1H-indole-2-carboxylic acid Example 42A is used instead of Example 31D in Example 31E Thus, this example was manufactured. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.16 (br, 1H), 8.21 (d, 1H), 7.87 (d, 1H), 7.78 (d, 2H), 7.70 (D, 1H), 7.63 (d, 2H), 7.50 (m, 4H), 7.39 (m, 1H), 7.27 (m, 1H), 7.13 (m, 1H) 6.88 (d, 1H), 4.90 (t, 2H), 4.21 (t, 2H), 2.39 (m, 2H).

(Example 43A)
Ethyl 1- (3- (naphthalen-1-yloxy) propyl) -3- (4- (trifluoromethoxy) phenyl) -1H-indole-2-carboxylate instead of ortho-tolylboronic acid in Example 31D, 4- (This example was prepared by using trifluoromethoxyphenylboronic acid.

(Example 43B)
1- (3- (1-naphthyloxy) propyl) -3- (4- (trifluoromethoxy) phenyl) -1H-indole-2-carboxylic acid Example 43A is used instead of Example 31D in Example 31E Thus, this example was manufactured. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.09 (br, 1H), 8.22 (d, 1H), 7.87 (d, 1H), 7.70 (m, 5H), 7.53 (M, 4H), 7.43 (m, 5H), 7.26 (m, 1H), 7.13 (m, 1H), 6.88 (d, 1H), 4.88 (t, 2H) 4.21 (t, 2H), 2.38 (m, 2H).

(Example 44A)
Ethyl 3- (2,3-dimethylphenyl) -1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate 2,3 in place of ortho-tolylboronic acid in Example 31D This example was prepared by using dimethylphenylboronic acid.

(Example 44B)
3- (2,3-Dimethylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid In Example 31E, Example 44A was used instead of Example 31D. This example was manufactured. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.67 (br, 1H), 8.24 (d, 1H), 7.87 (d, 1H), 7.66 (d, 1H), 7.53 (M, 3H), 7.38 (m, 1H), 7.23 (m, 1H), 7.15 (m, 1H), 7.10 (m, 2H), 7.03 (m, 1H) , 6.99 (d, 1H), 6.88 (d, 1H), 4.90 (t, 2H), 4.19 (t, 2H), 2.38 (m, 2H), 2.29 ( s, 3H), 1.93 (s, 3H).

(Example 45A)
Ethyl 3- (2,5-dimethylphenyl) -1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate In place of ortho-tolylboronic acid in Example 31D, 2,5- This example was prepared by using dimethylphenylboronic acid.

(Example 45B)
3- (2,5-Dimethylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid In Example 31E, Example 45A was used instead of Example 31D. This example was manufactured. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.69 (br, 1H), 8.19 (d, 1H), 7.87 (d, 1H), 7.66 (d, 1H), 7.49 (M, 3H), 7.38 (m, 1H), 7.23 (m, 1H), 7.15 (m, 1H), 7.07 (m, 3H), 6.93 (d, 1H) 6.88 (d, 1H), 4.90 (t, 2H), 4.19 (t, 2H), 2.38 (m, 2H), 2.27 (s, 3H), 1.96 ( s, 3H).

(Example 46A)
Ethyl 3- (3,4-dimethylphenyl) -1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate 3,4-in place of ortho-tolylboronic acid in Example 31D This example was prepared by using dimethylphenylboronic acid.

(Example 46B)
3- (3,4-Dimethylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid In Example 31E, Example 46A was used instead of Example 31D. This example was manufactured. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.89 (br, 1H), 8.22 (d, 1H), 7.87 (d, 1H), 7.64 (d, 1H), 7.45 (M, 5H), 7.22 (m, 1H), 7.17 (m, 2H), 7.07 (m, 2H), 6.88 (d, 1H), 4.84 (t, 2H) 4.19 (t, 2H), 2.36 (m, 2H), 2.27 (s, 3H), 2.25 (s, 3H).

(Example 47A)
3- (3,5-Dimethylphenyl) -1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate In Example 31D, instead of ortho-tolylboronic acid, 3,5- This example was prepared by using dimethylphenylboronic acid.

(Example 47B)
3- (3,5-Dimethylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid In Example 31E, Example 47A was used instead of Example 31D. This example was manufactured. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.92 (br, 1H), 8.19 (d, 1H), 7.87 (d, 1H), 7.64 (d, 1H), 7.48 (M, 5H), 7.23 (m, 1H), 7.08 (m, 1H), 6.97 (s, 3H), 6.87 (d, 1H), 4.84 (t, 2H) 4.19 (t, 2H), 2.36 (m, 2H), 2.31 (s, 3H).

(Example 48A)
Ethyl 3- (2,5-dimethoxyphenyl) -1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate In place of ortho-tolylboronic acid in Example 31D, 2,5- This example was prepared by using dimethoxyphenylboronic acid.

(Example 48B)
3- (2,5-dimethoxyphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid Example 48A was replaced by Example 48A instead of Example 31D. This example was manufactured. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.73 (br, 1H), 8.26 (m, 1H), 7.88 (m, 1H), 7.64 (d, 1H), 7.53 (M, 3H), 7.35 (m, 2H), 7.22 (m, 1H), 7.08 (m, 1H), 6.97 (d, 1H), 6.89 (m, 2H) 6.83 (d, 1H), 4.84 (t, 2H), 4.19 (t, 2H), 3.72 (s, 3H), 3.60 (s, 3H), 2.35 ( m, 2H).

(Example 49A)
Ethyl 3- (3,4-dimethoxyphenyl) -1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate 3,4-in place of ortho-tolylboronic acid in Example 31D This example was prepared by using dimethoxyphenylboronic acid.

(Example 49B)
3- (3,4-Dimethoxyphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid Example 49E was replaced by Example 49A instead of Example 31D. This example was manufactured. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.95 (br, 1H), 8.23 (m, 1H), 7.88 (m, 1H), 7.64 (d, 1H), 7.50 (M, 4H), 7.38 (m, 1H), 7.23 (m, 1H), 7.08 (m, 1H), 7.02 (d, 1H), 6.97 (d, 1H) 6.94 (dd, 1H), 6.88 (d, 1H), 4.84 (t, 2H), 4.19 (t, 2H), 3.81 (s, 3H), 3.74 ( s, 3H), 2.35 (m, 2H).

(Example 50A)
1- (4-Bromobutoxy) naphthalene This example was prepared by substituting 4-bromobutanol for 3-bromopropanol in Example 31A.

(Example 50B)
Ethyl 3-ortho-tolyl-1H-indole-2-carboxylate Example 31B (1.08 g), ortho-tolylboronic acid (1.1 g), (1,1′-bis (diphenylphosphino) ferrocene) dichloropalladium A mixture of (II) (140 mg) in dimethoxyethane: 2N Na ₂ CO ₃ aqueous solution (25 mL: 5 mL) was stirred at 80 ° C. under nitrogen for 16 h, diluted with ethyl acetate, washed with water and brine. The organic phase was dried (MgSO ₄ ), filtered and concentrated. The concentrate was purified by flash chromatography on silica gel with 0-10% ethyl acetate / hexane.

(Example 50C)
Ethyl 1- (4- (naphthalen-1-yloxy) butyl) -3-ortho-tolyl-1H-indole-2-carboxylate Example 50A was used instead of Example 31A in Example 31C and Instead, Example 50B was used to make this example.

(Example 50D)
3- (2-Methylphenyl) -1- (4- (1-naphthyloxy) butyl) -1H-indole-2-carboxylic acid In Example 31E, Example 50C was used instead of Example 31D. Examples were prepared. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.69 (br, 1H), 8.09 (d, 1H), 7.85 (d, 1H), 7.64 (d, 1H), 7.47 (M, 3H), 7.38 (m, 1H), 7.26 (m, 4H), 7.16 (m, 1H), 7.09 (m, 2H), 6.91 (d, 1H) 4.75 (t, 2H), 4.16 (t, 2H), 2.02 (m, 5H), 1.86 (m, 2H).

(Example 51A)
2- (4-Bromobutoxy) naphthalene This example was prepared by using 4-bromobutanol in place of 3-bromopropanol and 2-naphthol in place of 1-naphthol in Example 31A.

(Example 51B)
Ethyl 1- (4- (naphthalen-2-yloxy) butyl) -3-ortho-tolyl-1H-indole-2-carboxylate Example 51A was used instead of Example 31A in Example 31C, and Example 31B Instead, Example 50B was used to make this example.

(Example 51C)
3- (2-Methylphenyl) -1- (4- (2-naphthyloxy) butyl) -1H-indole-2-carboxylic acid In Example 31E, Example 51B was used instead of Example 31D. Examples were prepared. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.69 (br, 1H), 7.79 (m, 3H), 7.69 (d, 1H), 7.44 (m, 1H), 7.32 (M, 5H), 7.21 (m, 1H), 7.11 (m, 4H), 4.72 (t, 2H), 4.10 (t, 2H), 2.02 (s, 3H) 1.96 (m, 2H), 1.80 (m, 2H).

(Example 52A)
1- (4-Bromobutoxy) -2,3-dichlorobenzene In Example 31A, 4-bromobutanol was used instead of 3-bromopropanol, and 2,3-dichlorophenol was used instead of 1-naphthol. This example was manufactured.

(Example 52B)
Ethyl 1- (4- (2,3-dichlorophenoxy) butyl) -3-ortho-tolyl-1H-indole-2-carboxylate Example 31B was used instead of Example 31A in Example 31C. This example was made by using Example 50B instead of.

(Example 52C)
1- (4- (2,3-dichlorophenoxy) butyl) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid In Example 31E, Example 52B was used instead of Example 31D. This example was manufactured. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.66 (br, 1H), 7.67 (d, 1H), 7.34 (m, 1H), 7.26 (m, 4H), 7.18 (Dd, 1H), 7.14 (m, 1H), 7.08 (m, 3H), 4.71 (t, 2H), 4.10 (t, 2H), 2.01 (s, 3H) 1.95 (m, 2H), 1.76 (m, 2H).

(Example 53A)
1- (2- (2,4-Dichlorophenoxy) ethyl) -3-o-tolyl-1H-indole-2-carboxylate 1- (2-bromoethoxy)-in place of Example 31A in Example 31C This example was prepared using 2,4-dichlorobenzene and using Example 50B instead of Example 31B.

(Example 53B)
1- (2- (2,4-Dichlorophenoxy) ethyl) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid In Example 31E, Example 53A was used instead of Example 31D. This example was manufactured. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.68 (br, 1H), 7.75 (d, 1H), 7.49 (d, 1H), 7.35 (m, 1H), 7.28 (M, 3H), 7.22 (m, 1H), 7.14 (m, 2H), 7.07 (d, 2H), 5.07 (t, 2H), 4.45 (t, 2H) 2.01 (s, 3H).

(Example 54A)
1- (3- (2,4-Dichlorophenoxy) propyl) -3-ortho-tolyl-1H-indole-2-carboxylate 1- (3-bromopropoxy)-in place of Example 31A in Example 31C This example was prepared using 2,4-dichlorobenzene and using Example 50B instead of Example 31B.

(Example 54B)
1- (3- (2,4-Dichlorophenoxy) propyl) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid In Example 31E, Example 54A was used instead of Example 31D. This example was manufactured. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.68 (br, 1H), 7.64 (d, 1H), 7.59 (d, 1H), 7.35 (dd, 1H), 7.26 (M, 4H), 7.15 (m, 1H), 7.06 (m, 3H), 4.78 (t, 2H), 4.05 (t, 2H), 2.27 (m, 2H) 2.01 (s, 3H).

(Example 55)
1- (4- (2,4-Dichlorophenoxy) butyl) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid

(Example 55A)
1- (4- (2,4-Dichlorophenoxy) butyl) -3-ortho-tolyl-1H-indole-2-carboxylate 1- (4-bromobutoxy)-in place of Example 31A in Example 31C This example was prepared using 2,4-dichlorobenzene and using Example 50B instead of Example 31B.

(Example 55B)
1- (4- (2,4-Dichlorophenoxy) butyl) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid This example was prepared. By using Example 55A instead of Example 31D in Example 31E, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.68 (br, 1H), 7.64 (d, 1H), 7.54 (D, 1H), 7.33 (m, 2H), 7.24 (m, 3H), 7.11 (m, 4H), 4.70 (t, 2H), 4.07 (t, 2H) 2.01 (s, 3H), 1.94 (m, 2H), 1.74 (m, 2H).

(Example 56A)
Ethyl 3-benzyl-1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate Example 31C (100 mg), 0.5 M benzyl zinc (II) bromide in THF (1 .32 mL) and (1,1′-bis (diphenylphosphino) ferrocene) dichloropalladium (II) (18 mg) in THF (2 mL) were stirred at 60 ° C. for 16 h. The mixture was diluted with ethyl acetate and the organic phase was washed with water and brine, dried (MgSO ₄ ), filtered and concentrated. The concentrate was purified by flash chromatography on silica gel using 0-8% ethyl acetate / hexane.

(Example 56B)
3-Benzyl-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid This example was prepared by substituting Example 31D for Example 31E in Example 31E. . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.34 (br, 1H), 8.24 (d, 1H), 7.87 (m, 1H), 7.64 (d, 1H), 7.52 (M, 3H), 7.46 (d, 1H), 7.37 (m, 1H), 7.22 (m, 5H), 7.11 (m, 1H), 7.03 (m, 1H) 6.85 (d, 1H), 4.84 (t, 2H), 4.46 (s, 2H), 4.13 (t, 2H), 2.31 (m, 2H).

(Example 57A)
3- (2-Methylbenzyl) -1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate instead of benzylzinc (II) bromide in Example 56A (2-methyl This example was prepared by using (benzyl) zinc (II) bromide.

(Example 57B)
3- (2-Methylbenzyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid In Example 31E, Example 57A was used instead of Example 31D. Examples were prepared. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.11 (br, 1H), 8.24 (d, 1H), 7.87 (m, 1H), 7.61 (d, 1H), 7.52 (M, 2H), 7.46 (m, 1H), 7.37 (m, 2H), 7.16 (m, 2H), 7.02 (m, 2H), 6.92 (m, 1H) 6.86 (d, 1H), 6.66 (d, 1H), 4.88 (t, 2H), 4.40 (s, 2H), 4.13 (t, 2H), 2.38 ( s, 3H), 2.34 (m, 2H).

(Example 58A)
3- (3-Methylbenzyl) -1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate instead of benzylzinc (II) bromide in Example 56A (3-methyl This example was prepared by using (benzyl) zinc (II) bromide.

(Example 58B)
3- (3-Methylbenzyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid In Example 31E, Example 58A was used instead of Example 31D. Examples were prepared. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.24 (br, 1H), 8.24 (d, 1H), 7.87 (m, 1H), 7.62 (d, 1H), 7.52 (M, 3H), 7.46 (m, 1H), 7.37 (m, 1H), 7.16 (m, 1H), 7.03 (m, 4H), 6.92 (d, 1H) 6.85 (d, 1H), 4.84 (t, 2H), 4.40 (s, 2H), 4.13 (t, 2H), 2.31 (m, 2H), 2.20 ( s, 3H).

(Example 59A)
3- (4-Methylbenzyl) -1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate instead of benzylzinc (II) bromide in Example 56A (4-methyl This example was prepared by using (benzyl) zinc (II) bromide.

(Example 59B)
3- (4-Methylbenzyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid In Example 31E, Example 59A was used instead of Example 31D. Examples were prepared. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.23 (br, 1H), 8.24 (m, 1H), 7.87 (m, 1H), 7.62 (d, 1H), 7.52 (M, 3H), 7.46 (m, 1H), 7.37 (m, 1H), 7.16 (m, 1H), 7.11 (d, 1H), 7.01 (m, 3H) 6.85 (d, 1H), 4.84 (t, 2H), 4.41 (s, 2H), 4.13 (t, 2H), 2.31 (m, 2H), 2.20 ( s, 3H).

(Example 60A)
1- (3- (Naphthalen-1-yloxy) propyl) -3- (naphthalen-2-ylmethyl) -1H-indole-2-carboxylate instead of benzylzinc (II) bromide in Example 56A (naphthalene- This example was prepared by using 2-ylmethyl) zinc (II) bromide.

(Example 60B)
3- (2-Naphthylmethyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid In Example 31E, Example 60A was used instead of Example 31D. Examples were prepared. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.30 (br, 1H), 8.25 (m, 1H), 7.87 (m, 1H), 7.80 (m, 1H), 7.74 (M, 3H), 7.67 (d, 1H), 7.59 (d, 1H), 7.52 (m, 2H), 7.41 (m, 5H), 7.18 (m, 1H) 7.02 (m, 1H), 6.85 (d, 1H), 4.86 (t, 2H), 4.64 (s, 2H), 4.14 (t, 2H), 2.33 ( m, 2H).

(Example 61)
1- (3- (1-Naphtyloxy) propyl) -3- (2-phenylethyl) -1H-indole-2-carboxylic acid Example 66 (18 mg), cyclohexene (0.5 mL), Pd / C (10 %, 5 mg) in ethanol (2 mL) was heated at 110 ° C. for 20 min under microwave conditions (CEM Discover), filtered and concentrated. The product was purified by preparative reverse phase HPLC (Zorbax SB, C-18, 20% to 100% acetonitrile / water / 0.1% trifluoroacetic acid). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.15 (br, 1H), 8.23 (m, 1H), 7.87 (m, 1H), 7.68 (m, 1H), 7.53 (M, 3H), 7.45 (d, 1H), 7.37 (m, 1H), 7.26 (m, 4H), 7.18 (m, 2H), 7.06 (m, 1H) 6.85 (d, 1H), 4.83 (t, 2H), 4.12 (t, 2H), 3.30 (t, 2H), 2.83 (t, 2H), 2.33 ( m, 2H).

(Example 62)
1- (3- (1-Naphtyloxy) propyl) -3- (3-phenylpropyl) -1H-indole-2-carboxylic acid In Example 61, Example 67 was used instead of Example 66. Examples were prepared. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.07 (br, 1H), 8.23 (d, 1H), 7.87 (m, 1H), 7.59 (d, 1H), 7.55 (M, 3H), 7.44 (m, 1H), 7.35 (m, 1H), 7.26 (m, 2H), 7.18 (m, 4H), 7.06 (m, 1H) 6.82 (d, 1H), 4.83 (t, 2H), 4.12 (t, 2H), 3.08 (t, 2H), 2.65 (t, 2H), 2.29 ( m, 2H), 1.88 (m, 2H).

(Example 63A)
1- (2-Bromoethoxy) naphthalene This example was prepared by using 2-bromoethanol instead of 3-bromopropanol in Example 31A.

(Example 63B)
Ethyl 1- (2- (naphthalen-1-yloxy) ethyl) -3-ortho-tolyl-1H-indole-2-carboxylate Example 63A was used instead of Example 31A in Example 31C, and Example 31B Instead, Example 50B was used to make this example.

(Example 63C)
3- (2-Methylphenyl) -1- (2- (1-naphthyloxy) ethyl) -1H-indole-2-carboxylic acid Example 31D was used in Example 31 instead of Example 63B. Examples were prepared. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.82 (br, 1H), 7.88 (m, 2H), 7.79 (d, 1H), 7.43 (m, 3H), 7.33 (M, 4H), 7.21 (m, 1H), 7.12 (m, 3H), 6.94 (d, 1H), 5.22 (m, 2H), 4.50 (m, 2H) 1.95 (s, 3H).

(Example 64A)
2- (2-Bromoethoxy) naphthalene This example was prepared by using 2-naphthol in place of 1-naphthol and 2-bromoethanol in place of 3-bromopropanol in Example 31A.

(Example 64B)
Ethyl 1- (2- (naphthalen-2-yloxy) ethyl) -3-ortho-tolyl-1H-indole-2-carboxylate Example 64A was used instead of Example 31A in Example 31C and Instead, Example 50B was used to make this example.

(Example 64C)
3- (2-Methylphenyl) -1- (2- (2-naphthyloxy) ethyl) -1H-indole-2-carboxylic acid In Example 31, instead of Example 31D, Example 64B was used. Examples were prepared. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.77 (br, 1H), 7.78 (m, 4H), 7.43 (m, 1H), 7.37 (m, 1H), 7.29 (M, 4H), 7.21 (m, 1H), 7.14 (m, 1H), 7.09 (m, 2H), 7.02 (dd, 1H), 5.08 (m, 2H) 4.45 (m, 2H), 1.99 (s, 3H).

(Example 65A)
1- (2-bromoethoxy) -2,3-dichlorobenzene In Example 31A, using 2,3-dichlorophenol instead of 1-naphthol and using 2-bromoethanol instead of 3-bromopropanol, This example was manufactured.

(Example 65B)
Ethyl 1- (2- (2,3-dichlorophenoxy) ethyl) -3-ortho-tolyl-1H-indole-2-carboxylate Example 65B was used instead of Example 31A in Example 31C. This example was made by using Example 50B instead of.

(Example 65C)
1- (2- (2,3-dichlorophenoxy) ethyl) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid Example 65B was used instead of Example 31D in Example 31. This example was manufactured. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.68 (br, 1H), 7.75 (d, 1H), 7.35 (m, 1H), 7.24 (m, 4H), 7.13 (M, 3H), 7.09 (d, 2H), 5.08 (m, 2H), 4.48 (m, 2H), 2.01 (s, 3H).

Example 66
1- (3- (1-Naphtyloxy) propyl) -3-((E) -2-phenylvinyl) -1H-indole-2-carboxylic acid Example 31C (100 mg), (E) -styrylboronic acid ( 39 mg) and bis (triphenylphosphine) palladium (II) dichloride (8 mg) in 7: 3: 3 dimethoxyethane: ethanol: 1N aqueous LiOH (2 mL) at 130 ° C. under microwave conditions (CEM Discover) at 30 ° C. Heated for minutes. The mixture was quenched with 1N HCl and extracted with ethyl acetate. The extract was dried (Na ₂ SO ₄ ), filtered and concentrated. The concentrate was purified by reverse phase HPLC (Zorbax SB-C18, 20% to 100% acetonitrile / water / 0.1% trifluoroacetic acid) to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.59 (br, 1H), 8.24 (m, 1H), 8.15 (d, 1H), 7.94 (m, 1H), 7.87 (M, 1H), 7.69 (d, 1H), 7.59 (m, 2H), 7.53 (m, 2H), 7.46 (m, 1H), 7.40 (m, 3H) 7.28 (m, 3H), 7.21 (m, 1H), 6.87 (d, 1H), 4.87 (t, 2H), 4.17 (t, 2H), 2.34 ( m, 2H).

(Example 67)
1- (3- (1-Naphtyloxy) propyl) -3-((1E) -3-phenylprop-1-enyl) -1H-indole-2-carboxylic acid In Example 66 (E) -styrylboronic acid This example was prepared by using (E) -3-phenylprop-1-enylboronic acid instead of. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.37 (br, 1H), 8.22 (d, 1H), 7.87 (m, 2H), 7.61 (d, 1H), 7.51 (M, 2H), 7.45 (m, 1H), 7.35 (m, 5H), 7.20 (m, 3H), 7.10 (m, 1H), 6.85 (d, 1H) 6.45 (m, 1H), 4.81 (t, 2H), 4.13 (t, 2H), 3.59 (d, 2H), 2.30 (m, 2H).

Example 68
3-((E) -2-cyclohexylvinyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid Instead of (E) -styrylboronic acid in Example 66 ( E) This example was prepared by using 2-cyclohexylvinylboronic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.30 (br, 1H), 8.23 (m, 1H), 7.91 (d, 1H), 7.87 (m, 1H), 7.60 (D, 1H), 7.52 (m, 2H), 7.45 (d, 1H), 7.37 (t, 1H), 7.21 (t, 1H), 7.12 (t, 1H) 7.07 (dd, 1H), 6.85 (d, 1H), 6.25 (dd, 1H), 4.81 (t, 2H), 4.13 (t, 2H), 2.29 ( m, 2H), 2.17 (m, 1H), 1.81 (m, 2H), 1.75 (m, 2H), 1.65 (m, 1H), 1.33 (m, 2H), 1.22 (m, 3H).

(Example 69)
1- (3- (1-naphthyloxy) propyl) -3- (3- (piperidin-1-ylcarbonyl) phenyl) -1H-indole-2-carboxylic acid In Example 66 (E) -styrylboronic acid This example was prepared by using 3- (piperidine-1-carbonyl) phenylboronic acid instead. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.04 (br, 1H), 8.19 (d, 1H), 7.86 (d, 1H), 7.68 (d, 1H), 7.44 (M, 9H), 7.26 (t, 1H), 7.11 (t, 1H), 6.88 (d, 1H), 4.88 (t, 2H), 4.20 (t, 2H) 3.57 (br, 4H), 2.38 (m, 2H), 1.61 (br, 2H), 1.50 (br, 4H).

(Example 70)
3- (4-Fluoro-3- (morpholin-4-ylcarbonyl) phenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid In Example 66 (E)- This example was prepared by using 4-fluoro-3- (morpholine-4-carbonyl) phenylboronic acid instead of styrylboronic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.06 (br, 1H), 8.18 (d, 1H), 7.86 (m, 1H), 7.69 (d, 1H), 7.45 (M, 8H), 7.27 (m, 1H), 7.12 (t, 1H), 6.88 (d, 1H), 4.89 (t, 2H), 4.20 (t, 2H) 3.66 (s, 4H), 3.56 (br, 2H), 3.31 (br, 2H), 2.38 (m, 2H).

(Example 71)
3- (3-(((2-methoxyethyl) amino) carbonyl) phenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid In Example 66 (E)- This example was prepared by using 3- (2-methoxyethylcarbamoyl) phenylboronic acid instead of styrylboronic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (br, 1H), 8.52 (t, 1H), 8.25 (m, 1H), 7.93 (s, 1H), 7.86 (M, 2H), 7.68 (d, 1H), 7.49 (m, 6H), 7.25 (m, 1H), 7.11 (t, 1H), 6.89 (d, 1H) 4.89 (t, 2H), 4.20 (t, 2H), 3.46 (m, 4H), 3.26 (s, 3H), 2.38 (m, 2H).

(Example 72)
3- (3-((Dimethylamino) sulfonyl) phenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid Example 66 replaces (E) -styrylboronic acid This example was prepared using 3- (N, N-dimethylsulfamoyl) phenylboronic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.20 (br, 1H), 8.20 (m, 1H), 7.87 (m, 1H), 7.73 (m, 5H), 7.47 (M, 5H), 7.28 (m, 1H), 7.17 (m, 1H), 6.87 (m, 1H), 4.89 (m, 2H), 4.18 (m, 2H) 2.66 (s, 6H), 2.40 (m, 2H).

(Example 73)
3- (3- (morpholin-4-ylmethyl) phenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid In Example 66, instead of (E) -styrylboronic acid This example was prepared using 4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl) morpholine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.01 (br, 1H), 8.24 (m, 1H), 7.88 (m, 1H), 7.70 (d, 1H), 7.53 (M, 8H), 7.39 (t, 1H), 7.28 (m, 1H), 7.13 (t, 1H), 6.89 (d, 1H), 4.90 (t, 2H) 4.42 (s, 2H), 4.20 (t, 2H), 3.98 (br, 2H), 3.65 (br, 2H), 3.29 (br, 2H), 3.14 ( br, 2H), 2.38 (m, 2H).

(Example 74A)
1- (3- (Naphthalen-1-yloxy) propyl) -3- (piperidin-1-yl) -1H-indole-2-carboxylate Example 31C (100 mg), piperidine (57 mg), tris (dibenzylidene) A mixture of acetone) dipalladium (0) (20 mg), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (26 mg) and Cs ₂ CO ₃ (216 mg) in toluene (2 mL) For 48 hours. The mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated. The concentrate was purified by flash chromatography on silica gel with 0-10% ethyl acetate / hexane.

(Example 74B)
1- (3- (1-Naphtyloxy) propyl) -3-piperidin-1-yl-1H-indole-2-carboxylic acid Example 74A (30 mg) in 1N LiOH aqueous solution / methanol / THF (1 mL / 1 mL / 1 mL The mixture was stirred at room temperature overnight. The reaction mixture was acidified with 1N HCl (1 mL) and extracted with ethyl acetate. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated. The concentrate was purified by reverse phase HPLC (Zorbax SB-C18, 20% to 100% acetonitrile / water / 0.1% trifluoroacetic acid). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 16.82 (s, 1H), 8.08 (d, 1H), 7.96 (d, 1H), 7.85 (d, 1H), 7.69 (D, 1H), 7.48 (m, 3H), 7.36 (t, 1H), 7.24 (m, 1H), 7.13 (t, 1H), 6.83 (t, 1H) 4.89 (t, 2H), 4.16 (t, 2H), 3.24 (br, 4H), 2.33 (m, 2H), 1.70 (br, 6H).

(Example 75A)
Ethyl 3-morpholino-1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate This example was prepared by substituting morpholine for piperidine in Example 74A.

(Example 75B)
3-morpholin-4-yl-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid This example was obtained by substituting Example 75A for Example 74A in Example 74B. An example was manufactured. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 15.74 (s, 1H), 8.10 (d, 1H), 7.93 (d, 1H), 7.85 (m, 1H), 7.71 (D, 1H), 7.50 (m, 2H), 7.44 (d, 1H), 7.36 (t, 1H), 7.25 (m, 1H), 7.14 (m, 1H) 6.84 (d, 1H), 4.89 (t, 2H), 4.16 (t, 2H), 3.81 (t, 4H), 3.26 (t, 4H), 2.33 ( m, 2H).

(Example 76A)
Ethyl 1- (3- (naphthalen-1-yloxy) propyl) -3- (3- (trifluoromethoxy) phenylamino) -1H-indole-2-carboxylate In Example 74A, 3- (tri This example was prepared by using (fluoromethoxy) aniline.

(Example 76B)
1- (3- (1-Naphtyloxy) propyl) -3-((3- (trifluoromethoxy) phenyl) amino) -1H-indole-2-carboxylic acid Example 74B instead of Example 74A This example was manufactured by using 76A. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.23 (br, 1H), 8.24 (m, 1H), 8.08 (br, 1H), 7.87 (m, 1H), 7.64 (D, 1H), 7.52 (m, 2H), 7.46 (d, 2H), 7.37 (t, 1H), 7.28 (d, 1H), 7.20 (m, 2H) 7.00 (t, 1H), 6.85 (d, 1H), 6.74 (m, 2H), 6.63 (d, 1H), 4.85 (t, 2H), 4.15 ( t, 2H), 2.32 (m, 2H).

(Example 77A)
3- (4- (Methoxycarbonyl) piperidin-1-yl) -1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate In Example 74A, instead of piperidine, piperidine- This example was prepared by using methyl 4-carboxylate.

(Example 77B)
3- (4-Carboxypiperidin-1-yl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid Example 77A is used instead of Example 74A in Example 74B Thus, this example was manufactured. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 16.42 (s, 1H), 12.39 (s, 1H), 8.08 (d, 1H), 7.94 (d, 1H), 7.85 (M, 1H), 7.70 (d, 1H), 7.48 (m, 3H), 7.36 (t, 1H), 7.25 (m, 1H), 7.13 (t, 1H) 6.83 (d, 1H), 4.89 (t, 2H), 4.15 (t, 2H), 3.42 (m, 2H), 3.13 (m, 2H), 2.69 ( m, 1H), 2.33 (m, 2H), 2.05 (m, 2H), 1.72 (m, 2H).

(Example 79)
3-anilino-4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid

(Example 79A)
Methyl 1- (3- (naphthalen-1-yloxy) propyl) -3- (phenylamino) -4-o-tolyl-1H-indole-2-carboxylate Example 126C (42 mg, 0.079 mmol), aniline ( 8.71 μL, 0.095 mmol), xanthophos (4.14 mg, 7.15 μmol), diacetoxypalladium (1.071 mg, 4.77 μmol) and dioxane (2 mL) at 160 ° C. under microwave conditions for 30 minutes. Heated. The precipitate was removed by filtration and the filtrate was concentrated. The residue was purified by flash chromatography eluting with 1/1 dichloromethane / hexane to give the desired product.

(Example 79B)
3-anilino-4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid Example 79A (34.1 mg) and sodium hydroxide (0. (252 mL) in tetrahydrofuran (1 mL) and methanol (1.000 mL) was stirred overnight and acidified with HCl. The resulting mixture was concentrated and the residue was purified by RP HPLC on a C18 column (mobile phase: 10% to 100% acetonitrile / 0.1% aqueous TFA in 60 minutes). ¹ H NMR (400 MHz, dimethyl sulfoxide-D ₆ ) δ 13.11 (s, 1H), 8.21-8.31 (m, 1H), 7.86-7.90 (m, 1H), 7.65 (D, J = 7.98 Hz, 1H), 7.49-7.57 (m, 2H), 7.44-7.49 (m, 1H), 7.36-7.42 (m, 1H) 7.26 (dd, J = 8.29, 7.06 Hz, 1H), 6.92-7.00 (m, 1H), 6.80-6.91 (m, 4H), 6.70- 6.78 (m, 3H), 6.63 (s, 1H), 6.46 (t, J = 7.21 Hz, 1H), 6.06 (d, J = 7.67 Hz, 2H), 4. 75-5.07 (m, 2H), 4.20 (t, J = 5.68 Hz, 2H), 2.39 (t, J = 6.14 Hz, 2H), 1.87 (s, 3H).

(Example 80)
3- (3- (1-Naphtylthio) cyclohexyl) -1H-indole-2-carboxylic acid

(Example 80A)
Ethyl 3- (3-oxocyclohexyl) -1H-indole-2-carboxylate 1H- ethyl indole-2-carboxylate (2.953 g) and cyclohex-2-enone (1.004 mL) were added to acetonitrile (50 mL). Added to. Bismuth (III) trifluoromethanesulfonate (341 mg) was added and the solution was heated at 65 ° C. for 2 days. The solution was cooled, concentrated and purified by flash column chromatography on silica gel using 10-20% ethyl acetate / hexanes to give the title compound.

(Example 80B)
Ethyl 3- (3-hydroxycyclohexyl) -1H-indole-2-carboxylate Example 80A (931 mg) was added to methanol (20 mL), cooled to 0 ° C. and treated with sodium borohydride (247 mg). . The solution was mixed at 0 ° C. for 1 hour, quenched with 1M HCl, and extracted with 70% ethyl acetate (in hexane). The solution was dried over brine and anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure to give the title compound.

(Example 80C)
Ethyl 3- (3- (naphthalen-1-ylthio) cyclohexyl) -1H-indole-2-carboxylate 1,1 ′-(azodicarbonyl) -dipiperidine (188 mg) was added to tetrahydrofuran (5 mL) and cooled. The mixture was brought to 0 ° C. and treated with trimethylphosphine (1M toluene solution, 0.746 mL). The solution was mixed at 0 ° C. for 15 minutes. Naphthalene-1-thiol (120 mg) was added, followed by Example 80B (195 mg). The solution was warmed to room temperature and mixed overnight. The solution was concentrated and purified by flash column chromatography on silica gel using 10% ethyl acetate / hexanes to give the title compound.

(Example 80D)
3- (3- (1-Naphtylthio) cyclohexyl) -1H-indole-2-carboxylic acid Example 80C (64 mg) was dissolved in tetrahydrofuran (1 mL), water (0.33 mL) and methanol (0.33 mL). Lithium hydroxide monohydrate (31 mg) was added and the solution was mixed overnight at room temperature. The solution was made slightly acidic using 1M HCl, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure to give the title compound. ¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 12.95 (wide s, 1H), 11.35 (s, 1H), 8.52 (d, 1H), 7.94 (dd, 1H), 7 .84 (dd, 1H), 7.81 (d, 1H), 7.64-7.52 (m, 3H), 7.46 (dd, 1H), 7.38 (d, 1H), 7. 17 (td, 1H), 6.97 (td, 1H), 4.33 (m, 1H), 3.85 (wide s, 1H), 2.07-1.86 (m, 5H), 1. 83-1.65 (m, 3H).

(Example 81)
3- (3- (1-Naphtyloxy) cyclohexyl) -1H-indole-2-carboxylic acid

(Example 81A)
Ethyl 3- (3- (naphthalen-1-yloxy) cyclohexyl) -1H-indole-2-carboxylate In Example 80C, 1,1 ′-(azodicarbonyl) -dipiperidine, trimethylphosphine and naphthalene-1-thiol The title compound was prepared by using diethyl azodicarboxylate, triphenylphosphine and naphthalen-1-ol, respectively, instead of.

(Example 81B)
3- (3- (1-Naphtyloxy) cyclohexyl) -1H-indole-2-carboxylic acid The title compound was prepared by substituting Example 81A for Example 80D in Example 80D. ¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 12.94 (broad s, 1H), 11.34 (s, 1H), 8.47 (m, 1H), 7.89-7.83 (m, 2H), 7.54 (t, 2H), 7.46-7.36 (m, 3H), 7.20 (t, 1H), 7.00 (m, 2H), 5.06 (wide s, 1H), 4.54 (tt, 1H), 2.44 (td, 1H), 2.21-2.08 (m, 4H), 1.83-1.75 (m, 3H).

(Example 88)
1- (2-Methylbenzyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 13.06 (s, 1H), 8.18-8.25 (m, 1H), 7.84-7.90 (m, 1H), 7.78 (D, J = 7.80 Hz, 1H), 7.48-7.55 (m, 2H), 7.43-7.48 (m, 1H), 7.34-7.41 (m, 2H) 7.24 (t, J = 7.63 Hz, 1H), 7.18 (d, J = 7.46 Hz, 1H), 6.99-7.09 (m, 2H), 6.87 (t, J = 7.46 Hz, 2H), 5.92 (d, J = 7.46 Hz, 1H), 5.78 (s, 2H), 4.20 (t, J = 6.10 Hz, 2H), 3. 39 (t, J = 7.5 Hz, 2H), 2.40 (s, 3H), 2.20-2.29 (m, J = 1.70 Hz, 2H).

Example 89
1- (2- (Dimethylamino) ethyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 13.04 (bs, 1H), 8.18-8.25 (m, 1H), 7.81-7.91 (m, 1H), 7.68 (D, J = 7.9 Hz, 1H), 7.48-7.58 (m, 3H), 7.45 (d, J = 7.9 Hz, 1H), 7.34-7.42 (m, 1H), 7.27 (t, J = 7.7 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 6.3 Hz, 1H), 4. 79 (s, 1H), 4.56 (t, J = 5.9 Hz, 2H), 4.17 (t, J = 6.1 Hz, 2H), 3.66 (t, J = 5.8 Hz, 2H) ), 2.10-2.25 (m, 2H).

(Example 90)
1- (3-Methylbenzyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 13.17 (s, 1H), 8.14-8.28 (m, 1H), 7.79-7.93 (m, 1H), 7.74 (D, J = 7.8 Hz, 1H), 7.42-7.57 (m, 3H), 7.34-7.40 (m, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.96-7.06 (m, 2H), 6.83-6.91 (m, 2H), 6.71 (d, J = 7.5 Hz, 1H), 5.79 (s, 2H), 4.17 (t, J = 6.1 Hz, 2H), 3.33-3.41 (m, 2H), 2.24 ( s, 2H), 2.19 (s, 3H).

(Example 91)
1- (4-Methylbenzyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 13.14 (s, 1H), 8.10-8.28 (m, 1H), 7.79-7.95 (m, 1H), 7.73 (D, J = 7.9 Hz, 1H), 7.41-7.57 (m, 4H), 7.33-7.41 (m, 1H), 7.25 (t, J = 7.5 Hz, 1H), 7.02 (t, J = 7.7 Hz, 4H), 6.88 (t, J = 7.9 Hz, 4H), 5.77 (s, 2H), 4.17 (t, J = 6.1 Hz, 2H), 3.32-3.39 (m, 2H), 2.21-2.25 (m, 2H), 2.20 (s, 3H).

(Example 92)
1- (1,1′-biphenyl-2-ylmethyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 13.04 (s, 1H), 8.09-8.25 (m, 1H), 7.81-7.90 (m, 1H), 7.76 (D, J = 8.1 Hz, 1H), 7.41-7.56 (m, 8H), 7.33-7.41 (m, 1H), 7.18-7.31 (m, 4H) , 6.99-7.13 (m, 2H), 6.87 (d, J = 6.8 Hz, 1H), 6.17 (d, J = 7.8 Hz, 1H), 5.71 (s, 2H), 4.18 (t, J = 6.1 Hz, 2H), 3.33-3.41 (m, 2H), 2.15-2.28 (m, 2H).

(Example 93)
1- (1,1′-biphenyl-3-ylmethyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 13.12 (s, 1H), 8.11-8.34 (m, 1H), 7.80-7.92 (m, 1H), 7.74 (D, J = 8.1 Hz, 1H), 7.20-7.61 (m, 15H), 7.02 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 7. 5 Hz, 1H), 6.85 (d, J = 6.8 Hz, 1H), 5.91 (s, 2H), 4.18 (t, J = 6.1 Hz, 2H), 3.31-3. 46 (m, 2H), 2.12-2.34 (m, 2H).

(Example 94)
1- (1,1′-biphenyl-4-ylmethyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 13.20 (s, 1H), 8.13-8.30 (m, 1H), 7.80-7.94 (m, 1H), 7.68 -7.81 (m, 1H), 7.22-7.60 (m, 14H), 6.95-7.13 (m, 3H), 6.88 (d, J = 6.4 Hz, 1H) 5.88 (s, 2H), 4.19 (t, J = 6.1 Hz, 2H), 3.38 (t, J = 7.5 Hz, 2H), 2.15-2.32 (m, 2H).

(Example 95)
1- (2,4-Dimethylbenzyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 13.03 (s, 1H), 8.18-8.29 (m, 1H), 7.81-7.93 (m, 1H), 7.77 (D, J = 7.8 Hz, 1H), 7.31-7.60 (m, 5H), 7.17-7.29 (m, 1H), 6.94-7.09 (m, 2H) 6.88 (d, J = 6.4 Hz, 1H), 6.66 (d, J = 7.8 Hz, 1H), 5.84 (d, J = 7.8 Hz, 1H), 5.73 ( s, 2H), 4.19 (t, J = 6.1 Hz, 2H), 3.38 (t, J = 7.5 Hz, 2H), 2.35 (s, 3H), 2.18-2. 32 (m, 2H), 2.16 (s, 3H).

Example 96
1- (4-Carboxybenzyl) -3- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 13.04 (s, 1H), 12.93 (s, 1H), 8.06 to 8.30 (m, 1H), 7.69-7.94 (M, 4H), 7.43-7.58 (m, 4H), 7.33-7.41 (m, 1H), 7.27 (t, J = 7.1 Hz, 1H), 6.97 −7.12 (m, 3H), 6.88 (d, J = 6.8 Hz, 1H), 5.89 (s, 2H), 4.18 (t, J = 5.9 Hz, 2H), 3 .34-3.44 (m, 2H), 2.13-2.32 (m, 2H).

(Example 97)
1-((2S) -2-methyl-3- (1-naphthyloxy) propyl) -4- (2-methylphenyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 12.91 (s, 1H), 8.06-8.31 (m, 1H), 7.77-7.95 (m, 1H), 7.64 (D, J = 8.7 Hz, 1H), 7.42-7.59 (m, 3H), 7.18-7.43 (m, 5H), 6.97 (d, J = 6.7 Hz, 1H), 6.71-6.89 (m, 2H), 4.82-4.95 (m, 1H), 4.66-4.83 (m, 1H), 3.97-4.13 ( m, 2H), 2.59-2.78 (m, 1H), 1.98-2.15 (m, 3H), 1.07 (d, J = 6.7 Hz, 3H).

(Example 98)
1-((2R) -2-methyl-3- (1-naphthyloxy) propyl) -4- (2-methylphenyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 12.91 (s, 1H), 8.06-8.31 (m, 1H), 7.77-7.95 (m, 1H), 7.64 (D, J = 8.7 Hz, 1H), 7.42-7.59 (m, 3H), 7.18-7.43 (m, 5H), 6.97 (d, J = 6.7 Hz, 1H), 6.71-6.89 (m, 2H), 4.82-4.95 (m, 1H), 4.66-4.83 (m, 1H), 3.97-4.13 ( m, 2H), 2.59-2.78 (m, 1H), 1.98-2.15 (m, 3H), 1.07 (d, J = 6.7 Hz, 3H).

Example 99
3- (3- (1-Naphtyloxy) propyl) -1- (pyridin-4-ylmethyl) -1H-indole-2-carboxylic acid
¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 13.30 (brs, 1H) 8.61-8.69 (m, 2H) 8.19 (d, 1H) 7.78-7.90 (m, 2H) 7.26-7.57 (m, 8H) 7.10 (t, 1H) 6.89 (d, 1H) 6.02 (s, 2H) 4.21 (t, 2H) 3.40 ( t, 2H) 2.21-2.29 (m, 2H).

(Example 100)
3- (3- (1-Naphtyloxy) propyl) -1- (pyridin-2-ylmethyl) -1H-indole-2-carboxylic acid
¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 8.51-8.57 (m, 1H) 8.17-8.23 (m, 1H) 7.84-7.89 (m, 1H) 71-7.79 (m, 2H) 7.42-7.57 (m, 4H) 7.38 (t, 1H) 7.24-7.35 (m, 2H) 7.06 (t, 1H) 6.89 (d, 1H) 6.77 (d, 1H) 5.91 (s, 2H) 4.19 (t, 2H) 3.38 (t, 2H) 2.19-2.30 (m, 2H).

(Example 101)
1- (4-Methoxybenzyl) -3- (2- (1-naphthyloxy) ethoxy) -1H-indole-2-carboxylic acid

(Example 101A)
While stirring a solution of ethyl 1 - bromo-1-H-indole-2-carboxylate (9.45 g) in tetrahydrofuran (100 mL) to N-bromosuccinic acid (8.89 g, 50 mmol). ) Was added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue was diluted with water (100 mL) and diethyl ether (300 mL). The organic layer was washed with water, brine and dried over Na ₂ SO ₄ . After filtration, the title compound was obtained by concentration of the solvent.

(Example 101B)
Ethyl 3-bromo-1- (4-methoxybenzyl) -1H-indole-2-carboxylate To a solution of Example 101A (5.9 g) in N, N-dimethylformamide (50 mL) was added 1- (bromomethyl)- 4- methoxybenzene (4.85 g) and _Cs 2 plus _CO 3 a (25 g). The mixture was stirred at room temperature overnight. The mixture was diluted with ether (300 mL) and water (200 mL). The aqueous layer was extracted twice with ether. The combined extracts were washed with water (3 times), brine and dried over Na ₂ SO ₄ . Concentration of the solvent gave Example 101B.

(Example 101C)
1- (4-Methoxybenzyl) -3- (2- (naphthalen-1-yloxy) ethoxy) -1H-indole-2-carboxylate Example 101B (388 mg ) and 2- (naphthalen-1-yloxy) ethanol To a solution of (188 mg) in toluene (3 mL), 1,1′-binaphthyl-2-yldi-tert-butylphosphine (7.5 mg), palladium (II) acetate (5 mg) and Cs ₂ CO ₃ (488 mg). added. The mixture was purged with argon, stirred at room temperature and heated at 80 ° C. overnight. The mixture was then diluted with ethyl acetate (200 mL), washed with water, brine, and dried over Na ₂ SO ₄ . After concentration of the solvent, the residue was loaded onto a silica gel column and eluted with 5% ethyl acetate / hexane to give Example 101C.

(Example 101D)
1- (4-Methoxybenzyl) -3- (2- (1-naphthyloxy) ethoxy) -1H-indole-2-carboxylic acid Example 101C (80 mg) in tetrahydrofuran (2 mL), methanol (1 mL) and water ( To a solution in 1 mL) was added LiOH (100 mg). The mixture was stirred at room temperature overnight. The mixture was acidified with 5% HCl and extracted with ethyl acetate (200 mL). The organic layer was washed with water, brine and dried over Na ₂ SO ₄ . After concentration of the solvent, the residue was dissolved in DMSO / methanol (1: 1, 1.5 mL) and purified by reverse phase HPLC. ¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 12.99 (m, 1H), 8.01 (m, 1H), 7.86 (m, 1H), 7.73 (m, 1H), 7. 46 (m, 6H), 7.27 (m, 1H), 6.98 (m, 3H), 6.74 (m, 2H), 5.70 (s, 2H), 4.64 (m, 2H) ), 4.48 (m, 2H), 3.67 (s, 3H).

(Example 102)
1- (4-Methoxybenzyl) -3- (3- (1-naphthyloxy) prop-1-inyl) -1H-indole-2-carboxylic acid

(Example 102A)
Ethyl 1- (4-methoxybenzyl) -3- (3- (naphthalen-1-yloxy) prop-1-inyl) -1H-indole-2-carboxylate Example 101B (3.89 g) in acetonitrile (20 mL) To the medium solution was added Pd (PhCN) ₂ Cl ₂ (38 mg), dicyclohexyl (2 ′, 4 ′, 6′-triisopropylbiphenyl-2-yl) phosphine (143 mg) and Cs ₂ CO ₃ (3.91 g). It was. The mixture was purged with argon and stirred at room temperature for 25 minutes. Then 1- (prop-2-ynyloxy) naphthalene (2.2 g) was added to the mixture and it was purged again with argon. The mixture was stirred at 80 ° C. for 3 hours. The mixture was diluted with ethyl acetate (300 mL), washed with water, brine and dried over Na ₂ SO ₄ . After filtration, the solvent was concentrated and the residue was loaded onto a silica gel column and eluted with 5% ethyl acetate / hexane to give Example 102A.

(Example 102B)
1- (4-Methoxybenzyl) -3- (3- (1-naphthyloxy) prop-1-inyl) -1H-indole-2-carboxylic acid Example 102A substituting Example 102A for Example The title compound was prepared by ester hydrolysis as detailed in the procedure for 101D. ¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 13.57 (m, 1H), 8.20 (m, 1H), 7.90 (m, 1H), 7.57 (m, 6H), 7. 25 (m, 3H), 6.98 (d, 2H), 6.80 (d, 2H), 5.78 (s, 2H), 5.36 (s, 2H), 3.66 (s, 3H) ).

(Example 103)
4- (2-Methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 12.92 (m, 1H), 8.26 (m, 1H), 7.87 (m, 1H), 7.65 (m, 1H), 7. 38 (m, 9H), 6.98 (m, 1H), 6.89 (m, 1H), 6.78 (s, 1H), 4.91 (m, 2H), 4.19 (m, 2H) ), 2.37 (m, 2H), 2.09 (s, 3H).

(Example 104)
4- (2,6-Dimethylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 12.89 (m, 1H), 8.28 (m, 1H), 7.87 (m, 1H), 7.37 (m, 9H), 6. 86 (m, 2H), 6.58 (m, 1H), 4.91 (t, 2H), 4.17 (t, 2H), 2.38 (m, 2H), 1.87 (s, 6H) ).

(Example 105)
1- (3- (1-Naphthyloxy) propyl) -4- (1,3,5-trimethyl-1H-pyrazol-4-yl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 8.25 (m, 1H), 7.88 (m, 1H), 7.41 (m, 6H), 6.91 (m, 4H), 4. 89 (m, 2H), 4.20 (m, 2H), 3.76 (s, 3H), 2.35 (m, 2H), 2.10 (s, 3H), 2.01 (s, 3H) ).

(Example 106)
1- (3- (1-Naphtyloxy) propyl) -4- (2-oxocyclohexyl) -1H-indole-2-carboxylic acid

(Example 106A)
In ethanol (120 mL) a solution of 4-bromo -1H- indole-2-carboxylate Ethyl bromoacetate (42 _g), was added water (60 mL) a solution of NaN 3 (25g). The mixture was stirred at reflux for 4 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ether (300 mL) and water (200 mL). The aqueous layer was further extracted with ether. The combined extracts were washed with water (3 times), brine and dried over Na ₂ SO ₄ . After filtration, the solvent was carefully concentrated to give ethyl azidoacetate (26 g), which was dissolved in ethanol (100 mL), 2-bromobenzaldehyde (12.5 g) was added to the solution, and it was added sodium ethoxide. A solution of (produced from Na (5.2 g) and ethanol (60 mL)) was added dropwise to a cooled one (−15 ° C.). The mixture was stirred at 0 ° C. for 4 hours before being poured into a mixture of ice and saturated aqueous NH ₄ Cl. The mixture was filtered and the precipitate was washed with water, diluted with ethyl acetate and dried over Na ₂ SO ₄ . Concentration of the solvent gave a crude intermediate, which was dissolved in xylene (100 mL) and added dropwise to xylene refluxed under nitrogen. After the addition, the mixture was stirred at reflux overnight. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (2% ethyl acetate / hexane).

(Example 106B)
To a solution of ethyl 4-bromo-1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate Example 106A (5.5 g) in N, N-dimethylformamide (60 mL), 1- (3-Bromopropoxy) naphthalene (5.4 g) and Cs ₂ CO ₃ (22 g) were added. The mixture was stirred at room temperature overnight. The mixture was diluted with ether (300 mL) and water (200 mL). The aqueous layer was extracted twice with ether. The combined extracts were washed with water (3 times), brine and dried over Na ₂ SO ₄ . The mixture was concentrated to give the crude product, which was purified by flash chromatography (2% ethyl acetate / hexane).

(Example 106C)
Ethyl 1- (3- (naphthalen-1-yloxy) propyl) -4- (2-oxocyclohexyl) -1H-indole-2-carboxylate Example 106B (438 mg) and cyclohexanone (196 mg) in dioxane (3 mL). To the solution was added tris (dibenzylideneacetone) dipalladium (0) (5 mg), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (xanthophos, 7 mg) and Cs ₂ CO ₃ (652 mg). It was. The mixture was stirred overnight at 80 ° C. under nitrogen. After cooling, the reaction mixture was diluted with ethyl acetate and shaken with water. The product was extracted with ether (3 x 200 mL). The combined organic extracts were washed with water, brine and dried over Na ₂ SO ₄ . After filtration, the mixture was concentrated and flash column purified (3% ethyl acetate / hexane) to give Example 106C.

(Example 106D)
1- (3- (1-Naphtyloxy) propyl) -4- (2-oxocyclohexyl) -1H-indole-2-carboxylic acid Example 106C was used instead of Example 101C, and the procedure for Example 101D was followed. The title compound was prepared by the described ester hydrolysis. ¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 12.86 (m, 1H), 8.28 (m, 1H), 7.87 (m, 1H), 7.46 (m, 5H), 7. 17 (m, 2H), 6.89 (m, 2H), 4.87 (m, 2H), 4.17 (m, 3H), 2.70 (m, 1H), 2.04 (m, 9H) ).

(Example 107)
4- (2-Methylphenyl) -3- (morpholin-4-ylmethyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid

(Example 107A)
To a solution of methyl 4- bromo-3-formyl-1H-indole-2-carboxylate in methyl 4-bromo-1H-indole-2-carboxylate (4.09 g) in dichloromethane (60 mL) was added POCl ₃ (3.7 g). ) And N, N-dimethylformamide (1.76 g) were added. The mixture was stirred at reflux overnight. The mixture was diluted with ethyl acetate (300 mL) and 2M aqueous sodium acetate (200 mL). The mixture was stirred well for 1 hour. The aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water (3 times), brine and dried over Na ₂ SO ₄ . After filtration, concentration of the mixture gave the title compound, which was used in the next step without purification.

(Example 107B)
4-Bromo-3-formyl-1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate N, N-dimethylformamide of Example 107A (1.76 g) (10 mL) To the medium solution was added 1- (3-bromopropoxy) naphthalene (1.66 g) and Cs ₂ CO ₃ (6.10 g). The mixture was stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate (300 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water (3 times) and brine and dried over Na ₂ SO ₄ . After filtration, the solvent was concentrated to give the crude product, which was purified by column chromatography (5% ethyl acetate / hexane).

(Example 107C)
Methyl 3-formyl-1- (3- (naphthalen-1-yloxy) propyl) -4-o-tolyl-1H-indole-2-carboxylate Example 107B (0.5 g) and o-tolylboronic acid (175 mg) Of tris (dibenzylideneacetone) dipalladium (0) (25 mg), tri-t-butyl-phosphonium tetrafluoroborate (16 mg) and CsF (489 mg) were added to a mixture of The mixture was purged with argon and stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate (200 mL), washed with water and brine, and dried over Na ₂ SO ₄ . After filtration, Example 107C was obtained by solvent concentration and column purification (5% ethyl acetate / hexane).

(Example 107D)
4- (2-Methylphenyl) -3- (morpholin-4-ylmethyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid Example 107C (50 mg) of dichloroethane ( To a solution in 3 mL) was added sodium triacetoxyborohydride (35 mg) and morpholine (15 mg). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water, brine and dried over Na ₂ SO ₄ . The residue was dissolved in tetrahydrofuran (4 mL), methanol (2 mL) and water (2 mL), and LiOH (100 mg) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was neutralized with aqueous NH ₄ Cl and extracted with ethyl acetate (3 × 100 mL). The combined extracts were dried and concentrated to give the crude product, which was purified by RP HPLC. ¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 8.25 (m, 1H), 7.86 (m, 2H), 7.45 (m, 9H), 6.93 (m, 2H), 4. 99 (m, 2H), 4.47 (m, 1H), 4.25 (t, 2H), 3.60 (m, 10H), 2.43 (m, 2H), 1.92 (s, 3H ).

(Example 108)
4- (2-Methylphenyl) -1- (3- (1-naphthyloxy) propyl) -3- (pyrrolidin-1-ylmethyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 8.84 (m, 1H), 8.24 (m, 1H), 7.86 (m, 2H), 7.48 (m, 9H), 6. 95 (m, 2H), 4.99 (m, 2H), 4.47 (m, 1H), 4.26 (m, 2H), 2.77 (m, 2H), 2.42 (m, 2H) ) 1.92 (s, 3H), 1.61 (m, 4H).

(Example 109)
3-((Dimethylamino) methyl) -4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 8.58 (m, 1H), 8.27 (m, 1H), 7.84 (m, 2H), 7.44 (m, 9H), 6. 93 (m, 2H), 5.00 (m, 2H), 4.37 (m, 1H), 4.24 (m, 2H), 2.40 (m, 6H), 2.15 (m, 3H) ) 1.92 (s, 3H).

(Example 110)
3-((((cyclohexylmethyl) amino) methyl) -4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 8.35 (m, 2H), 7.90 (m, 1H), 7.77 (m, 1H), 7.43 (m, 9H), 6. 93 (m, 2H), 4.95 (m, 2H), 4.22 (m, 3H), 3.17 (m, 2H), 2.36 (m, 2H), 2.20 (m, 1H) ), 2.06 (m, 1H), 1.91 (m, 3H), 1.56 (m, 4H), 1.18 (m, 3H), 0.76 (m, 2H).

(Example 111)
4- (2-morpholin-4-ylcyclohexyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 9.69 (m, 1H), 8.24 (m, 1H), 7.88 (m, 1H), 7.49 (m, 7H), 7. 21 (m, 1H), 6.86 (m, 1H), 4.88 (m, 2H), 4.18 (m, 3H), 4.04 (m, 2H), 3.82 (m, 4H) ), 2.91 (m, 4H), 2.27 (m, 3H), 1.92 (m, 3H), 1.49 (m, 3H).

(Example 112)
4- (2-Methylphenyl) -3-((4-methylpiperazin-1-yl) methyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 8.25 (m, 1H), 7.88 (m, 1H), 7.73 (m, 1H), 7.40 (m, 8H), 6. 90 (m, 2H), 6.65 (m, 1H), 4.90 (m, 2H), 4.23 (m, 3H), 3.36 (m, 4H), 2.85 (m, 3H) ), 2.67 (s, 3H), 2.37 (m, 3H), 1.95 (s, 3H).

(Example 113)
4- (2-Methylphenyl) -1- (3- (1-naphthyloxy) propyl) -3- (piperidin-1-ylmethyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 8.26 (m, 1H), 7.86 (m, 2H), 7.45 (m, 10H), 6.93 (m, 2H), 4. 97 (m, 2H), 4.46 (m, 1H), 4.25 (m, 2H), 3.72 (m, 2H), 3.10 (m, 3H), 2.40 (m, 2H) ) 1.92 (s, 3H), 1.35 (m, 6H).

(Example 114)
4- (2-Methylphenyl) -3-((4-methylpiperidin-1-yl) methyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 8.27 (m, 1H), 7.86 (m, 2H), 7.44 (m, 8H), 6.95 (m, 2H), 4. 98 (m, 2H), 4.44 (m, 1H), 4.24 (m, 2H), 3.70 (m, 2H), 3.18 (m, 2H), 2.40 (m, 2H) ), 1.91 (s, 3H), 1.36 (m, 8H), 0.79 (m, 3H).

(Example 115)
3-((Benzyl (methyl) amino) methyl) -4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 8.23 (m, 1H), 7.83 (m, 2H), 7.45 (m, 10H), 7.19 (m, 5H), 6. 91 (m, 2H), 5.01 (m, 2H), 4.24 (m, 2H), 2.37 (m, 3H), 1.95 (m, 2H).

(Example 116)
4- (2-Methylphenyl) -3-((methyl (pyridin-2-ylmethyl) amino) methyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 8.57 (m, 1H), 8.23 (m, 1H), 7.84 (m, 3H), 7.47 (m, 8H), 7. 24 (m, 4H), 6.91 (m, 2H), 4.94 (m, 2H), 4.24 (m, 2H), 4.12 (m, 2H), 2.37 (m, 4H) ), 2.12 (s, 3H), 1.88 (s, 3H).

(Example 117)
4- (2-Methylphenyl) -3-((methyl (pyridin-3-ylmethyl) amino) methyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 9.32 (m, 1H), 8.78 (m, 1H), 8.69 (m, 1H), 8.25 (m, 1H), 8. 01 (m, 1H), 7.89 (m, 1H), 7.80 (m, 1H), 7.66 (m, 1H), 7.43 (m, 6H), 7.20 (m, 4H) ), 6.93 (m, 2H), 4.98 (m, 2H), 4.28 (m, 2H), 2.39 (m, 2H), 2.00 (s, 3H), 1.86 (S, 3H).

(Example 118)
4- (2-Methylphenyl) -3-((methyl (pyridin-4-ylmethyl) amino) methyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 8.76 (m, 2H), 8.23 (m, 1H), 7.82 (m, 2H), 7.48 (m, 7H), 7. 21 (m, 4H), 6.90 (m, 2H), 4.96 (m, 2H), 4.25 (m, 2H), 2.39 (m, 2H), 2.02 (s, 3H) ), 1.87 (s, 3H).

(Example 119)
4- (2- (4-Fluorophenyl) cyclohex-1-en-1-yl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, chloroform-d) δ 8.36 (m, 1H), 7.81 (m, 1H), 7.52 (m, 2H), 7.42 (m, 1H), 7.32 ( m, 2H), 7.20 (m, 1H), 6.96 (m, 3H), 6.65 (m, 4H), 4.81 (m, 2H), 4.06 (m, 2H), 2.51 (m, 4H), 2.38 (m, 2H), 1.89 (m, 4H).

(Example 120)
4- (2-Methyl-6-nitrophenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, chloroform-d) δ 8.39 (m, 1H), 7.80 (m, 2H), 7.49 (m, 7H), 7.29 (m, 1H), 7.03 ( s, 1H), 6.92 (m, 1H), 6.72 (m, 1H), 4.92 (m, 2H), 4.15 (m, 2H), 2.50 (m, 2H), 2.07 (s, 3H).

(Example 121)
4- (2-Chloro-6-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, dimethyl sulfoxide-d ₆ ) δ 8.28 (m, 1H), 7.88 (m, 1H), 7.65 (m, 1H), 7.40 (m, 8H), 6. 89 (m, 2H), 6.63 (s, 1H), 4.90 (m, 2H), 4.20 (m, 2H), 2.38 (m, 2H), 1.94 (s, 3H) ).

(Example 122)
1- (3- (1-Naphthyloxy) propyl) -4- (2- (4-nitrophenyl) cyclohex-1-en-1-yl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, chloroform-d) δ 8.37 (m, 1H), 7.81 (m, 3H), 7.52 (m, 2H), 7.32 (m, 5H), 7.10 ( m, 2H), 6.99 (m, 1H), 6.68 (m, 2H), 4.84 (m, 2H), 4.06 (m, 2H), 2.54 (m, 4H), 2.42 (m, 2H), 1.93 (m, 4H).

(Example 123)
4- (2- (3-methoxyphenyl) cyclohex-1-en-1-yl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, chloroform-d) δ 8.36 (m, 1H), 7.80 (m, 1H), 7.51 (m, 2H), 7.30 (m, 4H), 7.02 ( m, 1H), 6.89 (m, 1H), 6.65 (m, 3H), 6.48 (m, 2H), 4.81 (m, 2H), 4.06 (m, 2H), 3.42 (s, 3H), 2.52 (m, 4H), 2.40 (m, 2H), 1.92 (m, 4H).

(Example 124)
4- (5-Fluoro-2-methyl-3-((methylsulfonyl) methyl) phenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (300 MHz, chloroform-d) δ 8.36 (m, 1H), 7.81 (m, 1H), 7.48 (m, 4H), 7.32 (m, 2H), 7.18 ( m, 1H), 7.08 (m, 2H), 6.99 (m, 1H), 6.72 (m, 1H), 4.92 (m, 2H), 4.41 (m, 2H), 4.16 (m, 2H), 2.92 (s, 3H), 2.51 (m, 2H), 2.17 (s, 3H).

(Example 125)
4- (2-Methylphenyl) -1- (3- (1-naphthyloxy) propyl) -3-phenyl-1H-indole-2-carboxylic acid Example 126A (36 mg), phenylboronic acid (12.5 mg) , K ₂ CO ₃ (1M, 0.17 mL) and bis (triphenylphosphine) palladium (II) dichloride (7.2 mg), 1,2-dimethoxyethane (2.2 mL), ethanol (0.6 mL) and water (0.9 mL) of the mixture in the mixture was heated at 160 ° C. for 10 minutes in a microwave reactor (CEM Discover). The reaction mixture was acidified with dilute trifluoroacetic acid / methanol solution (3: 1) and concentrated. The residue was suspended in a mixture of dimethyl sulfoxide and methanol (1: 1) and filtered. The filtrate was purified by RP HPLC on a C18 column (mobile phase: 10% to 100% acetonitrile / 0.1% aqueous TFA in 60 minutes) to give the desired product. ¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 8.26-8.31 (m, 1H), 7.82-7.94 (m, 1H), 7.69 (d, J = 7.93 Hz, 1H), 7.50-7.58 (m, 2H), 7.46-7.49 (m, 1H), 7.41 (t, J = 7.93 Hz, 1H), 7.30 (dd, J = 8.39, 7.17 Hz, 1H), 6.87-6.94 (m, 3H), 6.78-6.87 (m, 7H), 6.72 (d, J = 7.63 Hz) 1H), 4.76-5.00 (m, 2H), 4.25 (t, J = 5.80 Hz, 2H), 2.38-2.45 (m, 2H), 1.73 (s) 3H).

(Example 126)
3-Bromo-4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid

(Example 126A)
4-O-tolyl-1H-indole-2-carboxylate methyl 4-bromo-1H-indole (1.5 g) and o-tolylboronic acid (1.135 g) in dioxane (20 mL) was added tri- (t -Butyl) phosphonium tetrafluoroborate (0.101 g), tris (dibenzylideneacetone) dipalladium (0) (0.159 g) and CsF (3.17 g) were added. The reaction mixture was immediately purged with nitrogen and 2 mL of methanol was added. The resulting mixture was stirred at room temperature for 3 hours and concentrated. The residue was purified by flash chromatography eluting with dichloromethane to give the desired product.

(Example 126B)
Methyl 3-bromo-4-o-tolyl-1H-indole-2-carboxylate A solution of Example 126A (205 mg) in dichloromethane (5 mL) and tetrahydrofuran (5 mL) at 0 ° C. in tetrahydrofuran (3 mL) Bromosuccinic acid (144 mg) was added dropwise. The mixture was stirred while the ice bath gradually reached room temperature. The reaction mixture was concentrated and the residue was dissolved in dichloromethane and purified by flash chromatography eluting with 0-100% dichloromethane / hexanes to give the desired product.

(Example 126C)
Methyl 3-bromo-1- (3- (naphthalen-1-yloxy) propyl) -4-o-tolyl-1H-indole-2-carboxylate Example 126B (1.14 g) and 1- (3-bromopropoxy Cesium carbonate (2.158 g) was added to a solution of naphthalene (0.922 g) in N, N-dimethylformamide (20 mL). The reaction was stirred at room temperature overnight, diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with 0% to 50% dichloromethane / hexanes to give the title product.

(Example 126D)
3-Bromo-4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid Example 126C (22 mg), NaOH (0.167 mL), methanol A mixture of (1.5 mL) and tetrahydrofuran (1.500 mL) was stirred at room temperature for 36 hours, acidified with HCl and concentrated. The residue was purified by RP HPLC on a C18 column (mobile phase: 10% to 100% acetonitrile / 0.1% aqueous TFA in 60 minutes) to give the title compound. ¹ H NMR (500 MHz, dichloromethane-d ₂ ) δ 8.30-8.40 (m, 1H), 7.79-7.85 (m, 1H), 7.56 (d, J = 8.54 Hz, 1H ), 7.47-7.55 (m, 2H), 7.43 (d, J = 8.24 Hz, 1H), 7.35 (t, J = 7.93 Hz, 1H), 7.28-7 .33 (m, 2H), 7.20-7.27 (m, 2H), 7.13-7.18 (m, 1H), 6.93 (d, J = 7.02 Hz, 1H), 6 .75 (d, J = 7.63 Hz, 1H), 4.78-5.03 (m, 2H), 4.16 (t, J = 5.65 Hz, 2H), 2.37-2.54 ( m, 2H), 2.01 (s, 3H).

(Example 128)
4- (2-Methylphenyl) -3-((4-methylphenyl) amino) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 13.20 (s, 1H), 8.21-8.32 (m, 1H), 7.84-7.92 (m, 1H), 7.63 (D, J = 8.54 Hz, 1H), 7.50-7.58 (m, 2H), 7.47 (d, J = 8.54 Hz, 1H), 7.39 (t, J = 7. 93 Hz, 1H), 7.19-7.29 (m, 1H), 6.94-7.03 (m, 1H), 6.82-6.92 (m, 4H), 6.72 (d, J = 7.02 Hz, 1H), 6.50-6.62 (m, 3H), 5.98 (d, J = 8.54 Hz, 2H), 4.66-5.08 (m, 2H), 4.19 (t, J = 5.80 Hz, 2H), 2.31-2.42 (m, 2H), 2.06 (s, 3H), 1.86 (s, 3H).

(Example 129)
3- (4-Hydroxyphenyl) -4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 12.71 (s, 1H), 8.91 (s, 1H), 8.24-8.37 (m, 1H), 7.86-7.92 (M, 1H), 7.66 (d, J = 8.24 Hz, 1H), 7.50-7.60 (m, 2H), 7.44-7.50 (m, 1H), 7.40. (T, J = 7.93 Hz, 1H), 7.27 (dd, J = 8.54, 7.02 Hz, 1H), 6.81-7.01 (m, 4H), 6.77 (d, J = 7.32 Hz, 2H), 6.59 (d, J = 7.63 Hz, 2H), 6.22 (d, J = 8.24 Hz, 2H), 4.61-5.08 (m, 2H) ), 4.24 (t, J = 5.80 Hz, 2H), 2.27-2.44 (m, 2H), 1.73 (s, 3H).

(Example 130)
3- (3-Hydroxyphenyl) -4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 12.79 (s, 1H), 8.79 (s, 1H), 8.14-8.47 (m, 1H), 7.83-7.92 (M, 1H), 7.67 (d, J = 8.24 Hz, 1H), 7.51-7.59 (m, 2H), 7.45-7.50 (m, 1H), 7.41. (T, J = 7.93 Hz, 1H), 7.28 (dd, J = 8.24, 7.02 Hz, 1H), 6.89-6.95 (m, 2H), 6.75-6. 87 (m, 4H), 6.53-6.61 (m, 1H), 6.27-6.33 (m, 2H), 6.18 (d, J = 7.32 Hz, 1H). 67-5.03 (m, 2H), 4.24 (t, J = 5.80 Hz, 2H), 2.28-2.42 (m, 2H), 1.79 (s, 3H).

(Example 131)
4- (2-Methylphenyl) -1- (3- (1-naphthyloxy) propyl) -3-pyridin-4-yl-1H-indole-2-carboxylic acid
¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 13.49 (s, br, 2H), 8.30 (d, J = 6.10 Hz, 2H), 8.25 (d, J = 7.93 Hz, 1H), 7.88 (d, J = 7.63 Hz, 1H), 7.82 (d, J = 8.54 Hz, 1H), 7.45-7.58 (m, 3H), 7.37- 7.44 (m, 2H), 7.34 (d, J = 5.19 Hz, 2H), 6.97-7.04 (m, 1H), 6.84-6.97 (m, 4H), 6.80 (d, J = 7.63 Hz, 1H), 4.82-5.09 (m, 2H), 4.28 (t, J = 5.65 Hz, 2H), 2.39-2.48 (M, 2H), 1.77 (s, 3H).

(Example 132)
4- (2-Methylphenyl) -1- (3- (1-naphthyloxy) propyl) -3-pyridin-3-yl-1H-indole-2-carboxylic acid
¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 13.27 (s, 1H), 8.41 (d, J = 5.19 Hz, 2H), 8.21-8.32 (m, 1H), 7 .78-7.92 (m, 3H), 7.50-7.59 (m, 2H), 7.47-7.50 (m, 1H), 7.37-7.44 (m, 3H) 6.95-7.02 (m, 1H), 6.88-6.95 (m, 4H), 6.80 (d, J = 7.63 Hz, 1H), 4.83-5.19 ( m, 2H), 4.28 (t, J = 5.80 Hz, 2H), 2.40-2.48 (m, 2H), 1.75 (s, 3H), J = 5.80 Hz, 2H) 2.41-2.48 (m, 2H), 1.75 (s, 1H).

(Example 133)
3-Cyano-4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid

(Example 133A)
Methyl 3-cyano-1- (3- (naphthalen-1-yloxy) propyl) -4-o-tolyl-1H-indole-2-carboxylate Example 126C (100 mg), dicyanozinc (222 mg) and Pd (PPh ₃ ) A mixture of ₄ (21.87 mg, 0.019 mmol) in N, N-dimethylformamide (4 mL) was heated in a microwave reactor (CEM Discover) at 180 ° C. for 400 seconds and concentrated. The residue was dissolved in dichloromethane and purified by flash chromatography eluting with 50% to 100% dichloromethane / hexanes to give the desired product.

(Example 133B)
3-Cyano-4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid Tetrahydrofuran of Example 133A (16 mg) and sodium hydroxide (200 μL) (0.5 mL) and a mixture in methanol (0.5 mL) were stirred overnight, neutralized with dilute HCl and concentrated. The residue was purified by RP HPLC to give the desired product. ¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 14.24 (s, 1H), 8.14 (d, J = 8.54 Hz, 1H), 7.86 (dd, J = 7.48, 5. 65 Hz, 2H), 7.35-7.61 (m, 5H), 7.18-7.36 (m, 3H), 7.12 (d, J = 7.32 Hz, 1H), 7.06 ( d, J = 7.02 Hz, 1H), 6.89 (d, J = 7.32 Hz, 1H), 4.77-5.18 (m, 2H), 4.24 (t, J = 0.03 Hz) 2H), 2.30-2.47 (m, 2H), 1.99 (s, 3H).

(Example 134)
3-Bromo-5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid

(Example 134A)
Ethyl 3-bromo-5-fluoro-1H-indole-2-carboxylate The title compound was prepared by substituting ethyl 5-fluoro-1H-indole-2-carboxylate in Example 126B for Example 126A. .

(Example 134B)
To a solution of Example 134A (465 mg) and 1- (3-bromopropoxy) naphthalene (431 mg) in N, N-dimethylformamide (10 mL) was added cesium carbonate (1059 mg). The reaction was stirred at room temperature overnight, diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by RP HPLC to give ethyl 3-bromo-5-fluoro-1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate. The ester was hydrolyzed with aqueous NaOH / tetrahydrofuran and methanol to give the title compound. ¹ H NMR (400 MHz, dimethyl sulfoxide-D ₆ ) δ 8.13 (d, J = 7.98 Hz, 1H), 7.85 (d, J = 7.67 Hz, 1H), 7.74 (dd, J = 9.21, 4.30 Hz, 1H), 7.42-7.58 (m, 3H), 7.37 (t, J = 7.98 Hz, 1H), 7.27 (dd, J = 8.90) 2.45 Hz, 1H), 7.10-7.20 (m, 1H), 6.85 (d, J = 7.36 Hz, 1H), 4.87 (t, J = 6.90 Hz, 2H) 4.14 (t, J = 5.83 Hz, 2H), 2.21-2.39 (m, 2H).

(Example 135)
5- (Benzyloxy) -1- (3- (1-naphthyloxy) propyl) -3- (2- (trifluoromethyl) phenyl) -1H-indole-2-carboxylic acid

Example 135A
By using ethyl 5- (benzyloxy) -1H-indole-2-carboxylate instead of Example 126A in Example 126B in ethyl 5- (benzyloxy) -3-bromo-1H-indole-2-carboxylate The title compound was prepared.

(Example 135B)
Ethyl 5- (benzyloxy) -3-bromo-1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate Example 135A (500 mg) and 1- (3-bromopropoxy) N naphthalene (354 mg), N- dimethylformamide (10 mL) was _added, was added Cs ₂ CO 3 (871mg). The reaction was stirred at room temperature overnight, diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with 0-50% dichloromethane / hexanes to give the desired product.

(Example 135C)
5- (Benzyloxy) -1- (3- (1-naphthyloxy) propyl) -3- (2- (trifluoromethyl) phenyl) -1H-indole-2-carboxylic acid Example 135B (30 mg), 2 -(Trifluoromethyl) phenylboronic acid (15.3 mg), tetrakis (triphenylphosphine) palladium (0) (3.1 mg) and cesium fluoride (16.3 mg) in dimethoxyethane (1.4 mL) and methanol ( The mixture in 0.7 mL) was heated in a microwave reactor (CEM Discover) for 30 minutes at 100 ° C. and concentrated. The residue was purified by flash chromatography eluting with 0-100% dichloromethane / hexane to give 5- (benzyloxy) -1- (3- (naphthalen-1-yloxy) propyl) -3- (2 Ethyl-(trifluoromethyl) phenyl) -1H-indole-2-carboxylate was obtained. The ester was hydrolyzed with aqueous NaOH / tetrahydrofuran and methanol to give the title compound. ¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 12.67 (s, 1H), 8.04-8.40 (m, 1H), 7.87 (d, J = 7.32 Hz, 1H), 7 .82 (d, J = 7.63 Hz, 1H), 7.69 (t, J = 7.32 Hz, 1H), 7.57-7.65 (m, 2H), 7.44-7.56 ( m, 3H), 7.26-7.41 (m, 7H), 6.97 (dd, J = 9.00, 2.29 Hz, 1H), 6.85 (d, J = 7.93 Hz, 1H) ), 6.55 (d, J = 2.14 Hz, 1H), 4.83-4.98 (m, 4H), 4.05-4.24 (m, 2H), 2.28-2.40. (M, 2H).

(Example 136)
5-Fluoro-3- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 12.87 (s, 1H), 8.17 (d, J = 8.24 Hz, 1H), 7.86 (d, J = 7.93 Hz, 1H) 7.74 (dd, J = 9.15, 4.27 Hz, 1H), 7.42-7.57 (m, 3H), 7.38 (t, J = 7.93 Hz, 1H), 7. 24-7.32 (m, 2H), 7.22 (t, J = 7.32 Hz, 1H), 7.07-7.15 (m, 2H), 6.87 (d, J = 7.32 Hz) 1H), 6.75 (dd, J = 9.31, 2.59 Hz, 1H), 4.77-5.03 (m, 2H), 4.18 (t, J = 5.80 Hz, 2H) 2.28-2.43 (m, 2H), 2.01 (s, 3H).

(Example 137)
5-Fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 13.08 (s, 1H), 8.21 (d, J = 7.93 Hz, 1H), 7.86 (d, J = 7.63 Hz, 1H) 7.65 (dd, J = 9.00, 4.12 Hz, 1H), 7.47-7.58 (m, 2H), 7.41-7.48 (m, 2H), 7.37 ( t, J = 7.78 Hz, 1H), 7.24 (s, 1H), 7.01-7.11 (m, 1H), 6.85 (d, J = 7.32 Hz, 1H). 88 (t, J = 6.87 Hz, 2H), 4.13 (t, J = 5.49 Hz, 2H), 2.21-2.37 (m, 2H).

(Example 138)
5-Fluoro-1- (3- (1-naphthyloxy) propyl) -3- (2- (trifluoromethyl) phenyl) -1H-indole-2-carboxylic acid
¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 12.89 (s, 1H), 8.19 (d, J = 8.24 Hz, 1H), 7.87 (d, J = 7.93 Hz, 1H) 7.82 (d, J = 7.63 Hz, 1H), 7.75 (dd, J = 9.15, 4.27 Hz, 1H), 7.69 (t, J = 7.48 Hz, 1H), 7.61 (t, J = 7.63 Hz, 1H), 7.43-7.57 (m, 3H), 7.38 (t, J = 7.93 Hz, 1H), 7.34 (d, J = 7.63 Hz, 1H), 7.07-7.16 (m, 1H), 6.85 (d, J = 7.63 Hz, 1H), 6.73 (dd, J = 9.31, 2. 29 Hz, 1H), 4.72-5.16 (m, 2H), 4.06-4.28 (m, 2H), 2.27-2.42 (m, 2H).

(Example 139)
5-Fluoro-3- (2-isopropylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 12.81 (s, 1H), 8.14 (d, J = 8.24 Hz, 1H), 7.86 (d, J = 7.93 Hz, 1H) 7.74 (dd, J = 9.15, 4.27 Hz, 1H), 7.50-7.55 (m, 1H), 7.44-7.50 (m, 2H), 7.32- 7.42 (m, 3H), 7.16-7.22 (m, 1H), 7.09-7.15 (m, 1H), 7.03-7.07 (m, 1H), 6. 86 (d, J = 7.63 Hz, 1H), 6.70 (dd, J = 9.15, 2.44 Hz, 1H), 4.72-5.06 (m, 2H), 4.17 (t , J = 5.80 Hz, 2H), 2.58-2.78 (m, 1H), 2.24-2.43 (m, 2H), 1.01 (d, J = 6.71 Hz, H), 0.94 (d, J = 7.02Hz, 3H).

(Example 140)
4- (2-Methylphenyl) -1- (3- (1-naphthyloxy) propyl) -3-((3- (trifluoromethoxy) phenyl) amino) -1H-indole-2-carboxylic acid
¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 13.09 (s, 1H), 8.20-8.35 (m, 1H), 7.81-7.92 (m, 1H), 7.67 (D, J = 8.54 Hz, 1H), 7.50-7.58 (m, 2H), 7.47 (d, J = 8.24 Hz, 1H), 7.39 (t, J = 7. 93 Hz, 1H), 7.27 (dd, J = 8.39, 7.17 Hz, 1H), 7.10 (s, 1H), 6.82-6.98 (m, 4H), 6.74- 6.82 (m, 3H), 6.30 (d, J = 8.24 Hz, 1H), 5.96 (d, J = 7.93 Hz, 1H), 5.90 (s, 1H), 4. 78-5.01 (m, 2H), 4.19 (t, J = 5.80 Hz, 2H), 2.31-2.44 (m, 2H), 1.89 (s, 3H).

(Example 141)
5- (Benzyloxy) -1- (3- (1-naphthyloxy) propyl) -3-((3- (trifluoromethoxy) phenyl) amino) -1H-indole-2-carboxylic acid
¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 8.22 (d, J = 7.67 Hz, 1H), 8.04 (s, 1H), 7.86 (dd, J = 7.21, 1. 69 Hz, 1H), 7.57 (d, J = 8.90 Hz, 1H), 7.48-7.55 (m, 2H), 7.43-7.47 (m, 1H), 7.28- 7.41 (m, 6H), 7.17 (t, J = 8.13 Hz, 1H), 6.92-6.99 (m, 1H), 6.84 (d, J = 7.67 Hz, 1H) ), 6.76 (d, J = 2.45 Hz, 1H), 6.64-6.72 (m, 2H), 6.61 (d, J = 6.14 Hz, 1H), 4.94 (s) 2H), 4.78-4.86 (m, 2H), 4.13 (t, J = 5.98 Hz, 1H), 2.24-2.35 (m, 2H).

(Example 142)
5- (Benzyloxy) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 8.23 (d, J = 8.29 Hz, 1H), 7.86 (d, J = 7.06 Hz, 1H), 7.49-7.58 ( m, 3H), 7.42-7.48 (m, 3H), 7.39 (t, J = 7.06 Hz, 3H), 7.29-7.36 (m, 1H), 7.23 ( d, J = 2.15 Hz, 1 H), 7.14 (s, 1 H), 6.91 (dd, J = 8.90, 2.46 Hz, 1 H), 6.84 (d, J = 7.98 Hz) 1H), 5.08 (s, 2H), 4.83 (t, J = 6.60 Hz, 2H), 4.12 (t, J = 6.29 Hz, 2H), 2.27-2.34 (M, 2H).

(Example 143)
5- (Benzyloxy) -3- (2-isopropylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 8.19 (d, J = 7.98 Hz, 1H), 7.86 (d, J = 7.36 Hz, 1H), 7.60 (d, J = 9.51 Hz, 1H), 7.43-7.56 (m, 3H), 7.25-7.43 (m, 8H), 7.13-7.21 (m, 1H), 7.04 ( d, J = 6.75 Hz, 1H), 6.98 (dd, J = 9.21, 2.45 Hz, 1H), 6.85 (d, J = 7.36 Hz, 1H), 6.53 (d , J = 2.15 Hz, 1H), 4.74-5.06 (m, 4H), 4.16 (t, J = 5.68 Hz, 2H), 2.64-2.81 (m, 1H) 2.27-2.42 (m, 2H), 1.00 (d, J = 7.06 Hz, 3H), 0.92 (d, J = 6.75 Hz, 3H).

(Example 144)
3- (2- (tert-Butoxymethyl) phenyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 8.22 (d, J = 7.67 Hz, 1H), 7.86 (d, J = 7.67 Hz, 1H), 7.70 (dd, J = 9.05, 4.14 Hz, 1H), 7.43-7.57 (m, 4H), 7.26-7.41 (m, 3H), 7.15 (dd, J = 7.36, 1 .23 Hz, 1H), 7.05-7.12 (m, 1H), 6.85 (d, J = 7.36 Hz, 1H), 6.77 (dd, J = 9.51, 2.45 Hz, 1H), 4.77-5.04 (m, 2H), 4.17 (t, J = 5.68 Hz, 2H), 4.11 (q, J = 10.74 Hz, 2H), 2.28- 2.42 (m, 2H), 0.75-0.88 (m, 9H).

(Example 145)
5-Fluoro-1- (3- (1-naphthyloxy) propyl) -3- (2-((3- (trifluoromethyl) phenoxy) methyl) phenyl) -1H-indole-2-carboxylic acid
¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 8.17 (d, J = 7.98 Hz, 1H), 7.85 (d, J = 7.36 Hz, 1H), 7.66 (dd, J = 9.21, 4.30 Hz, 1 H), 7.38-7.60 (m, 6 H), 7.21-7.37 (m, 3 H), 7.12 (d, J = 7.98 Hz, 1 H ), 7.03-7.11 (m, 1H), 6.92 (dd, J = 8.13, 1.99 Hz, 1H), 6.75-6.83 (m, 3H), 4.73 -5.00 (m, 4H), 3.96-4.15 (m, J = 6.44 Hz, 2H), 2.17-2.29 (m, 2H).

(Example 146)
5-Chloro-3- (2-isopropylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 8.10 (d, J = 8.29 Hz, 1H), 7.86 (d, J = 7.67 Hz, 1H), 7.75 (d, J = 8.90 Hz, 1 H), 7.52 (t, J = 6.90 Hz, 1 H), 7.43-7.49 (m, 2 H), 7.32-7.42 (m, 3 H), 7. 25 (dd, J = 8.90, 1.84 Hz, 1H), 7.15-7.22 (m, 1H), 7.04 (d, J = 6.75 Hz, 1H), 6.98 (d , J = 1.84 Hz, 1H), 6.85 (d, J = 7.36 Hz, 1H), 4.92 (t, J = 7.36 Hz, 2H), 4.17 (t, J = 5. 83 Hz, 2H), 2.59-2.74 (m, 1H), 2.30-2.44 (m, 2H), 1.01 (d, J = 6.75 Hz, 3H , 0.92 (d, J = 7.06Hz, 3H).

(Example 147)
5-Chloro-3- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 8.13 (d, J = 8.59 Hz, 1H), 7.86 (d, J = 8.59 Hz, 1H), 7.74 (d, J = 8.90 Hz, 1 H), 7.42-7.58 (m, 3 H), 7.38 (t, J = 7.98 Hz, 1 H), 7.17-7.34 (m, 4 H), 7. 12 (d, J = 7.06 Hz, 1H), 7.02 (d, J = 1.84 Hz, 1H), 6.87 (d, J = 7.36 Hz, 1H), 4.75-5.01 (M, 2H), 4.18 (t, J = 5.83 Hz, 2H), 2.32-2.43 (m, 2H), 1.99 (s, 3H).

(Example 148)
5-Hydroxy-3- (2-isopropylphenyl) -1- (3- (5,6,7,8-tetrahydronaphthalen-1-yloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 8.84 (s, 1H), 7.35-7.46 (m, 2H), 7.32 (t, J = 6.75 Hz, 1H), 7 .13-7.21 (m, 1H), 7.04 (d, J = 7.98 Hz, 1H), 6.98 (t, J = 8.13 Hz, 1H), 6.80 (d, J = 7.67 Hz, 1H), 6.63 (d, J = 8.29 Hz, 1H), 6.59 (d, J = 8.29 Hz, 1H), 6.37 (d, J = 2.15 Hz, 1H) ), 4.72 (t, J = 7.36 Hz, 2H), 3.92 (t, J = 5.98 Hz, 2H), 2.65-2.73 (m, 2H), 2.57-2 .64 (m, 2H), 2.14-2.25 (m, 2H), 1.64-1.78 (m, 4H), 1.04 (d, J = 6.75 Hz, 3 ), 0.98 (d, J = 6.75Hz, 3H).

(Example 149)
5-Hydroxy-3- (2-isopropylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid

(Example 149A)
5- (Benzyloxy) -3- (2-isopropylphenyl) -1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate 2- (trifluoromethyl) phenylboronic acid The title compound was prepared according to the procedure for Example 135C using 2- (isopropyl) phenylboronic acid instead of.

(Example 149B)
Ethyl 5-hydroxy-3- (2-isopropylphenyl) -1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate Example 149A (250 mg) and dihydroxypalladium (on carbon) A mixture of (20 mg) in tetrahydrofuran was stirred at room temperature for 29 hours under a hydrogen atmosphere (about 0.21 MPa (30 psi)). Insoluble material was removed by filtration, and the filtrate was concentrated. The residue was purified by flash chromatography eluting with dichloromethane to give the title compound.

(Example 149C)
5-hydroxy-3- (2-isopropylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid Example 149B (22 mg) in tetrahydrofuran (2 mL) and methanol (2 mL) ) Was added 0.3 mL of 10% NaOH. The reaction was heated at 70 ° C. for 24 hours, cooled, acidified with dilute aqueous HCl and concentrated. The residue was purified by RP HPLC to give the title compound. ¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 8.83 (s, 1H), 8.20-8.23 (m, 1H), 7.85-7.88 (m, 1H), 7.45 -7.55 (m, 5H), 7.34-7.40 (m, 2H), 7.28-7.34 (m, 1H), 7.17 (td, J = 7.36, 1. 23 Hz, 1H), 7.04 (dd, J = 7.52, 1.38 Hz, 1H), 6.85 (d, J = 7.36 Hz, 1H), 6.75 (dd, J = 8.90) 2.45 Hz, 1H), 6.37 (d, J = 2.15 Hz, 1H), 4.84 (t, J = 7.52 Hz, 2H), 4.15 (t, J = 5.68 Hz, 2H), 2.62-2.87 (m, 1H), 2.25-2.41 (m, 2H), 1.02 (d, J = 6.75 Hz, 3H), 0.9 (D, J = 7.06Hz, 3H).

(Example 150)
3- (2-Isopropylphenyl) -5- (4-morpholin-4-ylbutoxy) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid Example 149A (36 mg), A mixture of 1-chloro-4-iodobutane (0.043 mL) and cesium carbonate (116 mg) in N, N-dimethylformamide (2 mL) was stirred at room temperature overnight. Inorganic salts were removed by filtration. To the N, N-dimethylformamide solution was added morpholine (0.2 mL) and the resulting mixture was heated at 60 ° C. for 5 hours. The reaction mixture was concentrated and the residue was purified by RP HPLC on a C18 column (mobile phase: 10% to 100% acetonitrile / 0.1% aqueous TFA in 60 minutes) to give 3- (2-isopropylphenyl) Ethyl 5- (4-morpholinobutoxy) -1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate was obtained. The ester was hydrolyzed with aqueous NaOH in a mixture of tetrahydrofuran and methanol to give the title compound. ¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 9.52 (s, 1H), 8.20 (d, J = 8.29 Hz, 1H), 7.87 (d, J = 7.98 Hz, 1H) , 7.59 (d, J = 8.90 Hz, 1H), 7.43-7.57 (m, 3H), 7.30-7.43 (m, 3H), 7.14-7.23 ( m, 1H), 7.06 (d, J = 7.36 Hz, 1H), 6.89 (dd, J = 9.05, 2.30 Hz, 1H), 6.85 (d, J = 7.67 Hz) 1H), 6.43 (d, J = 2.45 Hz, 1H), 4.88 (t, J = 7.21 Hz, 2H), 4.15 (t, J = 5.83 Hz, 2H), 3 .89-4.03 (m, J = 11.17 Hz, 2H), 3.75-3.89 (m, 2H), 3.55-3.70 (m, 2H), 3 07-3.17 (m, 2H), 3.02 (s, br, 2H), 2.61-2.78 (m, 2H), 2.23-2.45 (m, 2H), 1. 60-1.85 (m, 4H).

(Example 151)
5-Fluoro-1- (3- (1-naphthyloxy) propyl) -3- (1,3,5-trimethyl-1H-pyrazol-4-yl) -1H-indole-2-carboxylic acid 1,3 5-trimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (43.2 mg), 3-bromo-5-fluoro-1- (3- (Naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate (the synthesis of this compound is described in Example 134B as an intermediate) (43 mg), dicyclohexyl (2 ′, A mixture of 6′-dimethoxybiphenyl-2-yl) phosphine (15.01 mg) and K ₃ PO ₄ (58.2 mg) in toluene (2.1 mL) was placed in a microwave reactor (CEM Heated at 110 ° C. for 2 hours. The reaction was loaded directly onto a silica cartridge and eluted with 0-25% ethyl acetate / dichloromethane. The recovered desired ester was hydrolyzed with NaOH in tetrahydrofuran-methanol-Et ₂ O at 50 ° C. overnight to give the title compound. ¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 8.15 (d, J = 8.90 Hz, 1H), 7.86 (d, J = 7.36 Hz, 1H), 7.71 (dd, J = 9.21, 4.30 Hz, 1H), 7.42-7.56 (m, 3H), 7.32-7.41 (m, 1H), 7.05-7.16 (m, 1H), 6.92 (dd, J = 9.36, 2.61 Hz, 1H), 6.86 (d, J = 7.36 Hz, 1H), 4.69-5.00 (m, 2H), 4.17 (T, J = 5.83 Hz, 2H), 3.72 (s, 3H), 2.27-2.43 (m, 2H), 1.99 (s, 3H), 1.90 (s, 3H) ).

(Example 152)
3- (2-Isopropylphenyl) -1- (3- (1-naphthyloxy) propyl) -5-phenyl-1H-indole-2-carboxylic acid 5-chloro-3- (2-isopropylphenyl) -1- (3- (Naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate (the synthesis of this compound was similar to the intermediate in Example 134) (56 mg), phenylboronic acid (26 mg ), Diacetoxypalladium (2.39 mg), dicyclohexyl (2 ′, 6′-dimethoxybiphenyl-2-yl) phosphine (8.74 mg) and K ₃ PO ₄ (67.8 mg) were synthesized by CEM microwave synthesis. It heated at 180 degreeC with the apparatus for 1 hour. The reaction was concentrated and the residue was purified by flash chromatography eluting with 0-50% dichloromethane / hexane. The recovered desired ester was saponified with NaOH in tetrahydrofuran-methanol-H ₂ O at 50 ° C. overnight to give the title compound. ¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 12.76 (s, 1H), 8.17 (d, J = 8.29 Hz, 1H), 7.86 (d, J = 7.67 Hz, 1H) 7.78 (d, J = 8.90 Hz, 1H), 7.43-7.58 (m, 6H), 7.32-7.44 (m, 5H), 7.28 (t, J = 7.21 Hz, 1H), 7.22 (d, J = 1.84 Hz, 1H), 7.16-7.21 (m, 1H), 7.06-7.12 (m, 1H), 6. 87 (d, J = 7.36 Hz, 1H), 4.95 (t, J = 7.06 Hz, 2H), 4.21 (t, J = 6.14 Hz, 2H), 2.68-2.82 (M, J = 7.06 Hz, 1H), 2.37-2.47 (m, 2H), 1.03 (d, J = 6.75 Hz, 3H), 0.96 (d, = 6.75Hz, 3H).

(Example 153)
3- (2,6-Dimethylphenyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 12.72 (s, 1H), 8.19 (d, J = 7.98 Hz, 1H), 7.86 (d, J = 7.36 Hz, 1H) 7.74 (dd, J = 9.21, 4.30 Hz, 1H), 7.42-7.56 (m, 3H), 7.37 (t, J = 7.98 Hz, 1H), 7. 05-7.20 (m, 4H), 6.84 (d, J = 7.67 Hz, 1H), 6.62 (dd, J = 9.05, 2.61 Hz, 1H), 4.93 (t , J = 6.90 Hz, 2H), 4.14 (t, J = 5.98 Hz, 2H), 2.26-2.44 (m, 2H), 1.87 (s, 6H).

(Example 154)
3- (2-Isopropylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 8.20 (d, J = 7.98 Hz, 1H), 7.83-7.91 (m, 1H), 7.67 (d, J = 8. 29Hz, 1H), 7.43-7.57 (m, 3H), 7.30-7.42 (m, 3H), 7.22-7.28 (m, 1H), 7.13-7. 22 (m, 1H), 6.98-7.11 (m, 3H), 6.86 (d, J = 7.36 Hz, 1H), 4.83-4.97 (m, 2H), 4. 18 (t, J = 5.98 Hz, 2H), 2.62-2.75 (m, 1H), 2.29-2.43 (m, 2H), 1.02 (d, J = 6.75 Hz) 3H), 0.94 (d, J = 7.06 Hz, 3H).

(Example 155)
1- (3- (1-naphthyloxy) propyl) -5-((1E) -pent-1-enyl) -1H-indole-2-carboxylic acid
¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 12.94 (s, 1H), 8.24 (d, J = 7.93 Hz, 1H), 7.87 (d, J = 7.63 Hz, 1H) 7.60 (s, 1H), 7.48-7.56 (m, 3H), 7.46 (d, J = 8.24Hz, 1H), 7.37 (t, J = 7.93Hz, 1H), 7.32 (dd, J = 8.85, 1.22 Hz, 1H), 7.20 (s, 1H), 6.85 (d, J = 7.63 Hz, 1H), 6.44 ( d, J = 15.87 Hz, 1H), 6.12-6.25 (m, 1H), 4.85 (t, J = 6.87 Hz, 2H), 4.13 (t, J = 5.80 Hz) 2H), 2.26-2.35 (m, 2H), 2.09-2.21 (m, 2H), 1.38-1.53 (m, 2H), 0.9 (T, J = 7.32Hz, 3H).

(Example 156)
3- (2,6-Dimethylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 12.59 (s, 1H), 8.21-8.27 (m, 1H), 7.83-7.89 (m, 1H), 7.68 (D, J = 8.59 Hz, 1H), 7.42-7.57 (m, 3H), 7.37 (t, J = 7.82 Hz, 1H), 7.20-7.27 (m, 1H), 7.07-7.18 (m, 3H), 6.94-7.05 (m, 2H), 6.84 (d, J = 7.67 Hz, 1H), 4.94 (t, J = 7.06 Hz, 2H), 4.15 (t, J = 5.83 Hz, 2H), 2.32-2.43 (m, 2H), 1.88 (s, 6H).

(Example 157)
1- (3- (1-naphthyloxy) propyl) -3- (1,3,5-trimethyl-1H-pyrazol-4-yl) -1H-indole-2-carboxylic acid
¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 8.20 (d, J = 7.98 Hz, 1H), 7.86 (d, J = 7.98 Hz, 1H), 7.66 (d, J = 8.90 Hz, 1H), 7.42-7.56 (m, 3H), 7.33-7.40 (m, 1H), 7.20-7.28 (m, 2H), 7.07 ( t, J = 7.52 Hz, 1H), 6.86 (d, J = 7.67 Hz, 1H), 4.73-5.02 (m, 2H), 4.18 (t, J = 5.83 Hz) 2H), 3.74 (s, 3H), 2.30-2.44 (m, 2H), 2.01 (s, 3H), 1.92 (s, 3H).

(Example 158)
3- (2-Chlorophenyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 13.00 (s, 1H), 8.18 (d, J = 7.98 Hz, 1H), 7.86 (d, J = 7.36 Hz, 1H) 7.75 (dd, J = 9.05, 4.14 Hz, 1H), 7.43-7.59 (m, 4H), 7.31-7.43 (m, 4H), 7.06- 7.17 (m, 1H), 6.78-6.92 (m, 2H), 4.64-5.21 (m, 2H), 4.19 (t, J = 5.83 Hz, 2H), 2.26-2.42 (m, 2H).

(Example 159)
3-((1E) -5- (Dimethylamino) pent-1-enyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid

(Example 159A)
(E) -3- (5-Chloropent-1-enyl) -5-fluoro-1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate 3-bromo-5- ethyl Fluoro-1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate (the synthesis of this compound is described in Example 134B as an intermediate) (404 mg), ( E) -2- (5-Chloropent-1-enyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.394 mL), diacetoxypalladium (19.28 mg), dicyclohexyl ( A mixture of 2 ′, 6′-dimethoxybiphenyl-2-yl) phosphine (70.5 mg) and K ₃ PO ₄ (547 mg) was added to a microwave reactor. (CEM Discover) at 100 ° C. for 1 hour. Insoluble material was removed by filtration and the filtrate was concentrated. The residue was purified by flash chromatography eluting with dichloromethane to give the title compound.

(Example 159B)
Example 159A (100 mg) in tetrahydrofuran (1 mL) was mixed with 1M dimethylamine / methanol (10 mL) and the resulting solution was heated at 50 ° C. for 3 days and concentrated. The residue was dissolved in tetrahydrofuran and methanol. 3 mL of 10% NaOH aqueous solution was added. The mixture was heated at 50 ° C. overnight and concentrated. The residue was purified by RP HPLC on a C18 column (mobile phase: 10% to 100% acetonitrile / 0.1% aqueous TFA in 60 minutes) to give the title compound. ¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 13.56 (s, br, 1H), 9.39 (s, br, 1H), 8.19 (d, J = 7.93 Hz, 1H), 7 .87 (d, J = 7.93 Hz, 1H), 7.64-7.73 (m, 2H), 7.43-7.59 (m, 3H), 7.38 (t, J = 7. 93 Hz, 1H), 7.04-7.18 (m, 2H), 6.85 (d, J = 7.32 Hz, 1H), 6.17-6.31 (m, 1H), 4.82 ( t, J = 7.02 Hz, 2H), 4.14 (t, J = 5.80 Hz, 2H), 3.06-3.16 (m, 2H), 2.80 (d, J = 4.58 Hz) 6H), 2.22-2.35 (m, 4H), 1.78-1.90 (m, 2H).

(Example 160)
3-((1E) -6-((2-carboxybenzoyl) amino) hex-1-enyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid acid

(Example 160A)
(E) -3- (6-Chlorohex-1-enyl) -5-fluoro-1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate in Example 159A (E ) -2- (5-Chloropent-1-enyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of (E) -2- (6-chlorohex-1-enyl) The title compound was prepared by using -4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

(Example 160B)
3-((1E) -6-((2-carboxybenzoyl) amino) hex-1-enyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid A mixture of acid example 160A (531 mg) and potassium 1,3-dioxoisoindoline-2-ide (213 mg) in N, N-dimethylformamide (10 mL) was heated at 80 ° C. for 8 hours. The reaction solution was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography eluting with 0-100% ethyl acetate / dichloromethane to give (E) -3- (6- (1,3-dioxoisoindoline-2-yl) hex- Ethyl 1-eneyl) -5-fluoro-1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate was obtained. This ester was dissolved in a mixture of tetrahydrofuran and methanol and 5 equivalents of aqueous NaOH (10%) was added. The mixture was heated at 50 ° C. for 5 hours. The reaction mixture was concentrated and the residue was dissolved in dimethyl sulfoxide and trifluoroacetic acid-methanol (3: 1) and purified by RP HPLC to give the title compound. ¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 13.06 (s, 2H), 8.25 (t, J = 5.52 Hz, 1H), 8.19 (dd, J = 7.83, 1. 38 Hz, 1H), 7.86 (dd, J = 7.21, 1.99 Hz, 1H), 7.74 (dd, J = 7.52, 1.38 Hz, 1H), 7.60-7.69. (M, 2H), 7.43-7.58 (m, 5H), 7.34-7.41 (m, 2H), 6.99-7.16 (m, 2H), 6.85 (d , J = 7.36 Hz, 1H), 6.15-6.32 (m, 1H), 4.65-4.96 (m, 2H), 4.13 (t, J = 5.68 Hz, 2H) 3.20-3.29 (m, 2H), 2.20-2.36 (m, 4H), 1.49-1.67 (m, 4H).

(Example 161)
3-((1E) -6-Aminohex-1-enyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid (E) -3- (6 -(1,3-Dioxoisoindoline-2-yl) hex-1-enyl) -5-fluoro-1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate (The synthesis of this compound is described in Example 160B as an intermediate), dissolved in a mixture of tetrahydrofuran and methanol and 5 equivalents of aqueous NaOH (10%) was added. The mixture was heated at 50 ° C. for 2 days. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC on a C18 column (mobile phase: 0% to 100% acetonitrile / 0.1% aqueous TFA in 60 minutes) to give the title compound. ¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 8.18 (d, J = 9.21 Hz, 1H), 7.82-7.89 (m, 1H), 7.57-7.70 (m, 4H), 7.42-7.55 (m, 4H), 7.37 (t, J = 7.67 Hz, 1H), 7.01-7.14 (m, 2H), 6.84 (d, J = 7.67 Hz, 1H), 6.14-6.29 (m, 1H), 4.80 (t, J = 7.83 Hz, 2H), 4.13 (t, J = 5.68 Hz, 2H) ) 2.70-2.97 (m, 2H), 2.11-2.37 (m, 4H), 1.41-1.76 (m, 4H).

(Example 162)
3- (6-Aminohexyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid (E) -3- (6- (1,3-di Oxoisoindoline-2-yl) hex-1-enyl) -5-fluoro-1- (3- (naphthalen-1-yloxy) propyl) -1H-indole-2-carboxylate (the synthesis of this compound is A mixture of (270 mg) (270 mg) and hydrazine (0.030 mL) in tetrahydrofuran (1.00 mL) and ethanol (3 mL) as described in Example 160B as an intermediate was heated at 50 ° C. overnight and concentrated. The residue was dissolved in tetrahydrofuran and methanol and 10% aqueous NaOH was added. The material was heated at 50 ° C. overnight and concentrated. The residue was purified by RP HPLC to give the title compound. ¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 8.17 (dd, J = 8.44, 1.07 Hz, 1H), 7.84-7.89 (m, 1H), 7.60 (dd, J = 9.21, 4.30 Hz, 1H), 7.41-7.56 (m, 4H), 7.32-7.40 (m, 1H), 7.01-7.11 (m, 1H) ), 6.84 (d, J = 7.06 Hz, 1H), 4.80 (t, J = 7.21 Hz, 2H), 4.12 (t, J = 5.83 Hz, 2H), 2.94 -3.06 (m, 2H), 2.75 (t, J = 8.29Hz, 2H), 2.20-2.35 (m, 2H), 1.43-1.63 (m, 4H) 1.27-1.36 (m, 4H).

(Example 163)
3- (5- (Dimethylamino) pentyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid Example 159 (45 mg) and Pt / C (5 %) (10 mg) in tetrahydrofuran (2 mL) was stirred under hydrogen (30 psi) at room temperature for 2.5 hours. Insoluble material was removed by filtration, and the filtrate was concentrated. The residue was purified by RP HPLC to give the desired product. ¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 9.28 (s, 1H), 8.17 (d, J = 7.67 Hz, 1H), 7.81-7.91 (m, 1H), 7 .61 (dd, J = 9.21, 4.30 Hz, 1H), 7.43-7.56 (m, 4H), 7.37 (t, J = 7.82 Hz, 1H), 7.01- 7.10 (m, 1H), 6.84 (d, J = 7.36 Hz, 1H), 4.80 (t, J = 6.90 Hz, 2H), 4.12 (t, J = 5.83 Hz) 2H), 2.91-3.07 (m, 4H), 2.19-2.35 (m, 2H), 1.50-1.69 (m, 4H), 1.25-1.39 (M, 2H).

(Example 164)
6-Chloro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 8.23-8.27 (m, 1H), 7.83-7.87 (m, 1H), 7.71 (s, 1H), 7.67 (D, J = 8.29 Hz, 1H), 7.43-7.54 (m, 3H), 7.36 (t, J = 7.98 Hz, 1H), 7.27 (s, 1H), 7 0.06 (dd, J = 8.59, 1.53 Hz, 1H), 6.84 (d, J = 7.36 Hz, 1H), 4.84 (t, J = 6.90 Hz, 2H), 4. 11 (t, J = 5.68 Hz, 2H), 2.27-2.33 (m, 2H).

(Example 165)
3- (2-((1E) -5- (Dimethylamino) pent-1-enyl) phenyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid acid
¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 12.90 (s, 1H), 9.20 (s, 1H), 8.16 (d, J = 8.24 Hz, 1H), 7.87 (d , J = 7.93 Hz, 1H), 7.72-7.80 (m, 1H), 7.67 (d, J = 7.63 Hz, 1H), 7.50-7.56 (m, 1H) 7.45-7.50 (m, 2H), 7.22-7.41 (m, 3H), 7.10-7.19 (m, 2H), 6.88 (d, J = 7. 63 Hz, 1H), 6.77 (dd, J = 9.46, 2.44 Hz, 1H), 6.04-6.21 (m, 2H), 4.90-5.00 (m, 1H), 4.82-4.91 (m, 1H), 4.20 (t, J = 5.80 Hz, 2H), 2.83-2.92 (m, 2H), 2.63-2.72 (m 6H), 2.34-2.41 (m, 2H), 1.97 (q, J = 6.61Hz, 2H), 1.55-1.65 (m, 2H).

(Example 166)
3- (2- (Dimethylamino) phenyl) -5-fluoro-1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ 8.18 (d, J = 7.98 Hz, 1H), 7.84-7.88 (m, 1H), 7.74 (dd, J = 8. 90, 4.30 Hz, 1H), 7.42-7.56 (m, 5H), 7.34-7.41 (m, 1H), 7.19-7.25 (m, 2H), 7. 09-7.15 (m, 1H), 6.95 (dd, J = 9.21, 2.45 Hz, 1H), 6.87 (d, J = 7.06 Hz, 1H), 4.87 (t , J = 7.06 Hz, 2H), 4.19 (t, J = 5.98 Hz, 2H), 2.63 (s, 6H), 2.33-2.42 (m, 2H).

(Example 167)
1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid
¹ H NMR (500 MHz, dimethyl sulfoxide-d ₆ ) δ 12.96 (s, 1H), 8.06-8.44 (m, 1H), 7.82-7.90 (m, 1H), 7.68 (D, J = 7.93 Hz, 1H), 7.60 (d, J = 8.54 Hz, 1H), 7.50-7.55 (m, 2H), 7.46 (d, J = 8. 24 Hz, 1 H), 7.37 (t, J = 7.93 Hz, 1 H), 7.28 (s, 1 H), 7.19 (t, J = 7.63 Hz, 1 H), 7.09 (t, J = 7.48 Hz, 1H), 6.84 (d, J = 7.63 Hz, 1H), 4.88 (t, J = 7.02 Hz, 2H), 4.13 (t, J = 5.80 Hz) 2H), 2.27-2.37 (m, 2H).

(Example 168)
1-methyl-5- (4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indol-2-yl) -1H-pyrazol-3-ol

(Example 168)
1-methyl-5- (4- (2-methylphenyl) -1- [3- (1-naphthyloxy) propyl] -1H-indol-2-yl) -1H-pyrazol-3-ol

(Example 168A)
3- (1- (3- (Naphthalen-1-yloxy) propyl) -4-o-tolyl-1H-indol-2-yl) -3-oxopropanoic acid ethyl 1- (3- (naphthalen-1-yloxy) ) Propyl) -4-o-tolyl-1H-indole-2-carboxylic acid (Example 103) (536 mg) and 1,1′-carbonyldiimidazole (200 mg) in tetrahydrofuran (10 mL) were stirred at room temperature overnight. did. To a suspension of potassium ethyl malonate (419 mg) in acetonitrile (10 mL) and triethylamine (0.515 mL) was added magnesium chloride (300 mg) and the mixture was stirred at room temperature for 4 hours and cooled in an ice bath. The solution prepared above was added dropwise to the first solution and the resulting suspension was stirred at room temperature for 3 days. The solvent was then removed under reduced pressure and the residue was taken up in toluene (50 mL), cooled (ice bath) and aqueous HCl (12%) was added slowly. The mixture was warmed to room temperature and extracted twice with ethyl acetate. The combined layers were washed with aqueous NaHCO ₃ and brine and dried over Na ₂ SO ₄ . After concentration of the solvent, the residue was loaded onto the column and eluted with 5% ethyl acetate / hexane to give the title compound.

(Example 168B)
1-methyl-5- (4- (2-methylphenyl) -1- [3- (1-naphthyloxy) propyl] -1H-indol-2-yl) -1H-pyrazol-3-ol Example 168A ( To a solution of 75 mg) in dioxane (2 mL) and water (1 mL) was added acetic acid (0.2 mL) and hydrazine monohydrate (0.2 mL). The mixture was stirred at 100 ° C. overnight and purified by RP HPLC to give the final product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.24 (m, 1H), 7.88 (m, 1H), 7.54 (m, 3H), 7.47 (d, 1H), 7.40 (D, 1H), 7.30 (m, 5H), 7.14 (t, 1H), 6.88 (d, 2H), 6.23 (s, 1H), 5.70 (s, 1H) 4.91 (m, 2H), 4.21 (m, 2H), 3.51 (m, 3H), 2.36 (m, 2H), 2.14 (s, 3H).

(Example 169)
4- (2-Methylphenyl) -1- (3- (1-naphthyloxy) propyl) -2- (1H-tetrazol-5-yl) -1H-indole

(Example 169A)
1- (3- (Naphthalen-1-yloxy) propyl) -1- (3- (naphthalen-1-yloxy) propyl) -4-o-tolyl-1H-indole-2-carboxamidooxalyl chloride (2 mL)- To a solution of 4-o-tolyl-1H-indole-2-carboxylic acid (Example 103) (0.9 g) in dichloromethane was added a few drops of N, N-dimethylformamide. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, the residue was dissolved in dichloromethane (20 mL) and concentrated ammonia / water solution (30 mL) was added to the cooled one (0 ° C.). After the addition, the mixture was stirred for 2 hours and extracted with ethyl acetate (200 mL). The organic layer was washed with water, brine and dried over Na ₂ SO ₄ . Distilling off the solvent gave the title compound.

(Example 169B)
1- (3- (Naphthalen-1-yloxy) propyl) -4-o-tolyl-1H-indole-2-carbonitrile A solution of Example 168A (880 mg) in tetrahydrofuran (10 mL) and dichloromethane (2 mL) was cooled. (0 ° C.), triethylamine (2 mL) was added thereto, and then trifluoroacetic anhydride (2 mL) was added dropwise. After the addition, the mixture was stirred at 0 ° C. for 3 hours. The mixture was then diluted with ethyl acetate (200 mL) and water (80 mL). The aqueous layer was extracted twice with ether. The combined extracts were washed with water (3 times), brine and dried over Na ₂ SO ₄ . The crude product was obtained by distilling off the solvent.

(Example 169C)
4- (2-Methylphenyl) -1- [3- (1-naphthyloxy) propyl] -2- (1H-tetrazol-5-yl) -1H-indole Example 168B (416 mg) of N, N-dimethyl To a mixture in formamide (10 mL) was added NaN ₃ (281 mg) and NH ₄ Cl (231 mg). The mixture was stirred at reflux overnight. The mixture was then concentrated under reduced pressure and the residue was partitioned between ethyl acetate (200 mL) and water (60 mL). The organic phase was washed with brine and dried over Na ₂ SO ₄ . After solvent concentration, the residue was dissolved in dimethyl sulfoxide / methanol (1: 1, 2 mL) and purified by RP HPLC. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.24 (m, 1H), 7.88 (m, 1H), 7.54 (m, 3H), 7.47 (d, 1H), 7.40 (D, 1H), 7.30 (m, 5H), 7.14 (t, 1H), 6.88 (d, 2H), 6.23 (s, 1H), 5.70 (s, 1H) 4.91 (m, 2H), 4.21 (m, 2H), 3.51 (m, 3H), 2.36 (m, 2H), 2.14 (s, 3H).

  The above description is intended to illustrate the present invention, but not to limit it. Variations and modifications apparent to those skilled in the art are intended to be included within the scope of the invention as defined by the accompanying claims.

Claims (2)

Less than:
3 - (3- (3- (trifluoromethyl) phenoxy) propyl)-1H-indole-2-carboxylic acid;
3- (3- (2-benzylphenoxy) propyl) -1H-indole-2-carboxylic acid;
3- (3- (2,3-dihydro-1H-inden-5-yloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3-((3-methyl-1-naphthyl) oxy) propyl) -1H-indole-2-carboxylic acid;
3- (3-((2-methyl-1-naphthyl) oxy) propyl) -1H-indole-2-carboxylic acid;
3- (3- (1-naphthylthio) propyl) -1H-indole-2-carboxylic acid;
3- (3-((7-methyl-2,3-dihydro-1H-inden-4-yl) oxy) propyl) -1H-indole-2-carboxylic acid;
3- (3- (5,6,7,8-tetrahydronaphthalen-1-yloxy) propyl) -1H-indole-2-carboxylic acid;
3 - (2-methylphenyl) -1- (3- (2-naphthyloxy) propyl)-1H-indole-2-carboxylic acid;
3- (2-methylphenyl) -1- (3- (5,6,7,8-tetrahydronaphthalen-1-yloxy) propyl) -1H-indole-2-carboxylic acid;
3- (2-methylphenyl) -1- (4- (1-naphthyloxy) butyl) -1H-indole-2-carboxylic acid;
3- (2-methylphenyl) -1- (4- (2-naphthyloxy) butyl) -1H-indole-2-carboxylic acid;
1- (4- (2,3-dichlorophenoxy) butyl) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid;
1- (2- (2,4-dichlorophenoxy) ethyl) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid;
1- (3- (2,4-dichlorophenoxy) propyl) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid;
1- (4- (2,4-dichlorophenoxy) butyl) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid;
3- (2-methylphenyl) -1- (2- (1-naphthyloxy) ethyl) -1H-indole-2-carboxylic acid;
3- (2-methylphenyl) -1- (2- (2-naphthyloxy) ethyl) -1H-indole-2-carboxylic acid;
1- (2- (2,3-dichlorophenoxy) ethyl) -3- (2-methylphenyl) -1H-indole-2-carboxylic acid;
3-((E) -2-cyclohexylvinyl) -1- (3- (1-naphthyloxy) propyl) -1H-indole-2-carboxylic acid;
3- (3- (1-naphthylthio) cyclohexyl) -1H-indole-2-carboxylic acid;
3- (3- (1-naphthyloxy) cyclohexyl) -1H-indole-2-carboxylic acid;
1- (4-methoxybenzyl) -3- (2- (1-naphthyloxy) ethoxy) -1H-indole-2-carboxylic acid;
1- (4-methoxybenzyl) -3- (3- (1-naphthyloxy) prop-1-inyl) -1H-indole-2-carboxylic acid;
5-hydroxy-3- (2-isopropylphenyl) -1- (3- (5,6,7,8-tetrahydronaphthalen-1-yloxy) propyl) -1H-indole-2-carboxylic acid;
1-methyl-5- (4- (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -1H-indol-2-yl) -1H-pyrazol-3-ol; A compound selected from the group consisting of (2-methylphenyl) -1- (3- (1-naphthyloxy) propyl) -2- (1H-tetrazol-5-yl) -1H-indole, or treatment of the compound Top acceptable salt.   A pharmaceutical composition comprising an excipient and a therapeutically effective amount of a compound according to claim 1 or a therapeutically acceptable salt.